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New Research on Lemtrada Reveals Insights into the Cause of Potential Side Effects

Researchers in the U.K. have evaluated additional findings about the immune-system impacts of Lemtrada® (alemtuzimab, Sanofi Genzyme), a disease-modifying therapy for treating people with relapsing MS.

The team used data from phase 3 clinical trials submitted to the European Medicines Agency during the drug’s successful approval process. Some of this data was previously reported at medical meetings and in Lemtrada’s prescribing information.

Among their findings, they report that Lemtrada caused long-term reduction of specific immune cells (memory B and T cells, including regulatory T cells). They also found that the body rapidly repopulated an overabundance of immature B cells.

They propose that the blockade of memory B and T cells drives the beneficial effects of Lemtrada.

They also speculate that the known potential side effect for autoimmune thyroid disease and other autoimmune disorders may be triggered by the overabundance of immature B cells that occurs when there are few regulatory T cells to keep them in check.

Studies like this one, which reveal more information about a therapy’s mode of action, are important and may also lead to insights about how to reduce side effects.

Drs. Klaus Schmierer, David Baker and others at the Queen Mary University of London report their findings in JAMA Neurology, published online June 12, 2017.

Read the open-access paper in JAMA Neurology
Read about Lemtrada
Read more about treating MS

Lemtrada is a registered trademark of Sanofi Genzyme

Interesting Results…

Gene That Boosts Resistance to Malaria linked to Susceptibility to MS and Lupus in Sardinia

Researchers from Italy found a strong association between the gene that instructs the molecule “BAFF” and susceptibility to MS and lupus in studies of nearly 6,000 people in Sardinia. The BAFF gene is crucial to activation of immune B cells and is also associated with resistance to malaria. Malaria was common in Sardinia until it was eradicated in 1950. The rates of MS and certain immune-mediated diseases are high in Sardinia. Further research is necessary to confirm whether this high rate is related to BAFF, and whether MS could be treated by a therapy that targets BAFF.

Read more about this study from the Genetic Literacy Project

Read the scientific summary of the paper in The New England Journal of Medicine

Read more about efforts to end MS forever

 
 

Novel Protein Identified Inside Cells During MS Inflammation May Help Explain Nerve Damage

Researchers from the University of Alberta in Canada report that levels of Rab32 – a protein that directs traffic between cell organs – are increased in sites of active inflammation in brain tissue obtained from people with MS and in mouse models of MS-like disease. This increase was linked to the destruction of nerve cells. If the results are confirmed, this knowledge could explain part of the neurodegenerative process that leads to progression of disability in MS and could be a target for development of effective MS treatments.

Read more on ReliaWire
Read the open access paper in Journal of Neuroinflammation
Read more about Research to stop MS in its tracks

Study Finds That Some Family Members of People with MS Show Possible Early Signs of the Disease without Symptoms

Summary

  • As part of a large-scale “Genes & Environment in MS” (GEMS) study to understand factors that lead to the development of multiple sclerosis, researchers analyzed the genes and backgrounds of individuals who had no symptoms of MS, but who had close family members with MS.
  • Based on that analysis, researchers identified a group of 40 women at higher risk for developing MS, and 25 women at lower risk. Extensive neurological testing and MRI scanning uncovered possible neurological abnormalities in the higher risk group, and MRI abnormalities in a small proportion of both groups.
  • “At this time, we are developing strategies to manage the risk of MS, but there is, as yet, no specific recommendation,” explains co-author Dr. Phillip De Jager. “Family members should be reassured that the vast majority of family members will not develop MS.”
  • The team (including Zongqi Xia, MD, PhD, of Brigham and Women’s Hospital, and Daniel S. Reich, MD, PhD, of National Institute of Neurological Disorders and Stroke, Bethesda, MD) has published results in JAMA Neurology (published online January 17, 2017).
  • This study was supported by the National MS Society and the National Institutes of Health, and the Society helped to recruit participants. Two of the study authors – Daniel S. Reich, MD, PhD, and Philip L. De Jager, MD, PhD – are winners of the prestigious Barancik Prize for Innovation in MS Research.

Background: An individual’s risk of developing MS increases if a close family member has MS. There is currently no way to predict which family members will develop MS. The goal of the Genes & Environment in MS (GEMS) study is to identify the genetic, environmental and immune profiles that may increase a person’s risk of developing MS.  Researchers are recruiting 5,000 subjects who have at least one first-degree relative with a diagnosis of MS. The GEMS Study is gathering genetic material (DNA) and environmental exposure history from participants as well as blood samples and brain magnetic resonance imaging (MRI) as an option. Investigators are classifying participants using the Genetic and Environmental Risk Score for MS Susceptibility (GERSMS), an experimental approach which incorporates genetic information and environmental exposures to identify people at higher or lower risk of developing MS.

The Study: As part of this large-scale, ongoing study, researchers looked at 65 women who are first-degree relatives of people with MS. The GERSMS indicated that 40 of these women were at higher risk of developing MS, and 25 women were at lower risk of developing MS. These women underwent a comprehensive neurologic examination and MRI scans.

Women in the higher risk group had less than normal vibration sensitivity in their big toes, a finding that indicates potential nerve dysfunction. A small percentage of the women in both groups had more MRI abnormalities associated with MS than one would expect to find in the general population.

The team (Zongqi Xia, MD, PhD, of Brigham and Women’s Hospital, Boston, MA, and Daniel S. Reich, MD, PhD, of National Institute of Neurological Disorders and Stroke, Bethesda, MD) has published results in JAMA Neurology (published online January 17, 2017).

This study was supported by the National MS Society and the National Institutes of Health, and the Society helped to recruit participants. Two of the study authors – Daniel S. Reich, MD, PhD, and Philip L. De Jager, MD, PhD – are winners of the prestigious Barancik Prize for Innovation in MS Research.

Next Steps:  In this study, women at high risk for MS showed possible early manifestations of the disease. “The goal of the Genes & Environment Study is to understand the sequence of events that leads someone to develop MS,” explains co-author Dr. De Jager. “At this time, we are developing strategies to manage the risk of MS, but there is, as yet, no specific recommendation. Family members should be reassured that the vast majority of family members will not develop MS.” He notes that the study did not test the possibility of preventive strategies, such as vitamin D supplementation.  “Taking vitamin D is good for bone health, and MS family members should discuss taking such supplements with their physician.”

Read more about research to find the genetic and environmental underpinnings of MS

 

New Study: Resilience in People with Chronic Disease is Linked to Social Satisfaction and Quality of Life – Not Physical Function

Summary

  • A survey of more than 1500 people with MS and other chronic diseases shows that resilience (the ability to solve problems and bounce back from difficult situations) is linked to satisfaction with social roles (such as work and family responsibilities) and quality of life, but not to physical function.
  • Understanding factors that promote resilience may help people with MS to not only cope with unpredictable changes in health and abilities, but to thrive in spite of these changes.  Learn more about how the resilience factor can help you to thrive. Watch an education program on Resilience: Addressing the Challenges of MS.
  • The team (Samuel Battalio, BS, and colleagues at the University of Washington) has published results in Archives of Physical Medicine and Rehabilitation (2016 Dec 16).

Background: Research on psychosocial issues forms a cornerstone of finding life-changing solutions for people with MS. MS can have a significant impact on a person’s emotions, not only because MS is unpredictable and challenging to live with, but because it affects parts of the brain that control mood. This study specifically looked at factors that can affect resilience (i.e., the ability tackle problems, find solutions and bounce back from difficult situations).

The Study: The team reviewed information on 1574 people with MS, muscular dystrophy, post poliomyelitis syndrome, and spinal cord injury, which was gathered from an ongoing survey that is tracking people in the United States who are aging with physical disabilities. Information was collected on resilience using a clinical scale, and on other factors (including physical function, satisfaction with social roles – meaning work and family responsibilities, and quality of life) using questionnaires that assess how people report their own health status.

The results suggest that people who reported significantly greater satisfaction with social roles and significantly greater quality of life had significantly higher resilience. This relationship was slightly different between men and women, in that men who expressed greater levels of satisfaction with social roles reported higher levels of resilience. Surprisingly, noted the authors, resilience was not significantly greater in people who reported better physical function.

The team (Samuel Battalio, BS, and colleagues at the University of Washington) has published results in Archives of Physical Medicine and Rehabilitation (2016 Dec 16).

Next Steps: The authors note that resilience is complex, and that further research could help uncover particular aspects of resilience that may be most beneficial to individuals.  Understanding factors that promote resilience may help people with MS to not only cope with unpredictable changes in health and abilities, but to thrive in spite of these changes.

There are behaviors that can help promote individuals’ resilience:

New Results Show that Magnetic Stimulation of Brain May Improve Working Memory and Brain Connectivity in People with MS

Summary

  • People with MS, but not healthy controls, showed improvements in working memory, brain activity, and “connectivity” (how parts of the brain interact with one another), after treatment with Repetitive Transcranial Magnet Stimulation (rTMS). This device generates electromagnet pulses that stimulate brain activity.
  • rTMS may have a future role in cognitive rehabilitation in people with MS, but further, larger studies are necessary to confirm the safety and effectiveness of this intervention and its long-term effects.
  • The team (Hanneke Hulst, MD, of VU Medical Center in Amsterdam, and others) has published results in Journal of Neurology, Neurosurgery, and Psychiatry (Published Online First: 14 December 2016).

Background: Repetitive Transcranial Magnet Stimulation (rTMS) was approved by the FDA as a treatment for major depression. A device that generates electromagnet pulses is placed on the scalp with the idea of stimulating specific brain activity. Studies have shown that people with MS who received rTMS showed significant decreases in depression. This team looked at whether rTMS improved working memory (short-term memory needed for tasks such as mental arithmetic), which can be affected in people with MS.

The Study: Investigators administered rTMS – or a “sham” version of lower intensity – to an area of the brain associated with working memory in17 people with MS and 11 healthy controls. None of the participants showed signs of impaired memory at the outset of the study. A potential adverse event of rTMS is seizures, so participants were excluded if they were taking medicine that put them at risk for seizures, or had MS brain lesions in particular areas. Before and after, participants underwent imaging and extensive neuropsychological testing aimed at investigating memory. They also completed a working memory task while undergoing functional MRI, which measures brain activity during tasks.

At the beginning of the study, there were no differences in working memory between people with MS and controls. After treatment, the results suggested improvements among people with MS in working memory, brain activity, and “connectivity” (how parts of the brain interact with one another). These changes were not seen in controls.

The team (Hanneke Hulst, MD, of VU Medical Center in Amsterdam, and others) has published results in Journal of Neurology, Neurosurgery, and Psychiatry

Next Steps: The authors comment that this small study implies that rTMS may play a future role in cognitive rehabilitation in people with MS. However, the study is limited by the small sample size and the fact that participants did not have obvious cognitive problems. Further studies that address these factors are necessary to confirm the safety and effectiveness of this intervention for people with MS and its long-term impact on day to day activities.

Read more about cognitive changes that affect people with MS

 

Positive Results Announced from Clinical Trial of BAF-312 (Siponimod) in Secondary Progressive MS

Summary

Results presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) provided additional details from a 60-month, phase III clinical trial of the experimental oral therapy siponimod (BAF312, Novartis Pharmaceuticals AG) involving 1,651 people with secondary progressive MS.

The trial met its primary endpoint of reducing the risk of disability progression compared with inactive placebo. Those on active treatment had a 21% reduced risk of disability progression compared to those on placebo. Secondary endpoints suggested that those on active therapy had 23.4% lower average change in brain volume and reduced lesion volume.

The therapy was generally well tolerated and similar to adverse events reported for similar compounds.

Details

Background: Siponimod (BAF312) is an experimental immune system-modulating therapy that was designed to be a more selective sphingosine 1-phosphate receptor modulator than Gilenya® (fingolimod, Novartis International AG). Gilenya, was approved in 2010 for adults with relapsing forms of MS to reduce the frequency of clinical relapses and to delay the accumulation of physical disability. Siponimod previously demonstrated safety and efficacy on MRI scans in a phase II study in people with relapsing-remitting MS (The Lancet Neurology, 2013 Aug;12(8):756-67).  Siponimod is thought to act by retaining certain white blood cells in the body’s lymph nodes, keeping them out of circulation and from entering the central nervous system. Siponimod also distributes effectively to the central nervous system (brain and spinal cord) where it may have direct anti-inflammatory or other effects.

The Study: Participants were randomly assigned to take siponimod or placebo capsules daily for up to 60 months. The primary endpoint of the study was reducing the risk of disability progression, as measured by the EDSS scale at three months. Secondary endpoints included reducing the risk of disability progression as measured by the EDSS at six months versus placebo, the risk of worsening mobility as measured by the timed 25-foot walk test, disease activity as observed on MRI scans, relapse rate, and safety/ tolerability.

Results:  Results were presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on September 17, 2016. The trial met its primary endpoint of reducing the risk of disability progression compared with inactive placebo. Those on active treatment had a 21% reduced risk of disability progression (confirmed at 3 months) compared to those on placebo. Secondary endpoints suggested that those on active therapy had at 26% reduced risk of disability progression (confirmed at 6 months), a 23.4% lower average change in brain volume, and reduced MRI-detected brain lesion volume. There was no significant difference seen between groups in the timed 25-foot walk. Relapse rates were significantly lower in those taking siponimod.

Safety: The therapy was generally well tolerated and similar to adverse events reported for similar compounds. Serious adverse events occurred in 16.7% of participants. The serious adverse events reported to be more likely for those taking siponimod included nervous system disorders and infections.

Comment:
“These results suggest a modest benefit for people with secondary progressive MS, which is a positive step forward in the global effort to speed solutions for people living with this chronic form of the disease,” said Timothy Coetzee, PhD, Chief Advocacy, Services and Research Officer at the National MS Society. “We look forward to learning additional details about its potential benefit and safety.”

Low-fat, plant-based diet in multiple sclerosis: A randomized controlled trial

Publication History

Published Online: July 06, 2016

http://www.msard-journal.com/article/S2211-0348(16)30100-6/fulltext#s0005

The role of diet in ameliorating the severity of multiple sclerosis (MS) has been long debated, but there remains a paucity of relevant research. Observational studies by Dr. Roy Swank, published between 1953 and 2003, suggested significantly reduced MS disease activity and disability progression and longer survival in people following a diet low in total and saturated fat compared with those who did not (Swank, 1953, Swank and Goodwin, 2003, Swank, 1970). Swank’s diet book, last published in 1987, remains popular among patients with MS. However, this approach to treating MS has never been subjected to a well-controlled clinical trial.

The supposed large clinical effect of the Swank low fat diet led to our hypothesis that a very-low-fat, plant-based diet might have a large effect on MRI activity. We conducted a pilot study to explore the tolerability and potential benefits of a very-low saturated fat, plant-based diet followed for 12 months by people with relapsing-remitting MS (RRMS) with the primary endpoint being brain MRI disease activity.

 

MS Trial Alert: Researchers Recruiting People with Relapsing MS for Antibody Study

Summary: Investigators at seven sites in the United States are recruiting at least 24 people with relapsing MS for a study of ublituximab (TG Therapeutics, Inc.), an experimental monoclonal antibody administered via intravenous infusion. At most, 100 people will be enrolled.

Rationale: Ublituximab is a new monoclonal antibody that binds to a molecule (CD20) on the surface of immune cells called B cells, and depletes them from circulation. B cells have several functions including making antibodies, and evidence suggests they play a role in immune-system mediated damage to brain and spinal cord tissues in MS. Other therapies targeting B cells (rituximab, ocrelizumab) have shown some benefit in clinical trials. Ublituximab binds to CD20 in a unique way, and thus may have greater B cell depletion capabilities than similar agents. Clinical trials are ongoing in people with blood cancer as well.

Eligibility and Details: Participants should be aged 18 to 55, have a diagnosis of relapsing MS, and have had more than one relapse in the previous two years. Further enrollment criteria are available from the contact below.

Participants are initially randomly assigned to receive either ublituximab or placebo infusions (infusions range from 1 to 4 hours).  After 28 days, participants receiving placebo will receive ublituximab.

The primary outcomes being measured are the levels of B cell depletion, and the number of participants who experience adverse events. Secondary outcomes include monitoring relapses and MRI-detected disease activity.

Contact: To learn more about the enrollment criteria for this study, and to find out if you are eligible to participate, please contact Koby Mok, PhD, via e-mail at kmok@tgtxinc.com, or by phone at 949-422-2468.

Sites are enrolling in the following cities:
Fort Collins, CO
Lexington, KY
San Antonio, TX
Knoxville, TN
Columbus, OH
Phoenix, AZ
Round Rock, TX

Download a brochure that discusses issues to think about when considering enrolling in an MS clinical trial (PDF).

Study Shows Expansion of Stem Cell Clinics in the U.S. and the Need for Better Oversight

Researchers have published a paper describing the proliferation of stem cell clinics in the United States and ethical issues and regulatory concerns that come with marketing unproven treatments for many conditions. Their study shows that many different types of unproven stem cell treatments are being offered, and highlights concerns for the safety of people who undergo these treatments.

There is exciting progress being made through innovative research related to the potential of many types of stem cells for slowing MS disease activity and for repairing damage to the nervous system. At present, there are no approved stem cell therapies for MS. People need the best available information to understand this exciting area of research and make decisions related to this complex issue.

The paper’s findings support the need for stem cell therapy to be explored in the context of carefully conducted clinical trials that can determine what the optimal cells, delivery methods, safety and actual effectiveness of cell therapies might be for people with MS.

Positive Results from Study of Bone Marrow-Derived Stem Cells in People with Aggressive, Relapsing MS

Summary

  • Researchers in Canada have published results of a long-term trial of an individuals’ own (autologous) hematopoietic (blood cell-producing) stem cell transplantation. The study involved 24 people with aggressive relapsing-remitting MS whose disease was not controlled with available therapies.
  • Three years after the procedure, 70% remained free of disease activity, with no relapses, no new MRI-detected inflammatory brain lesions, and no signs of progression.
  • None of the surviving participants, who were followed for 4 to 13 years after the procedure, experienced clinical relapses or required MS disease-modifying therapies to control their disease, and 40% experienced reductions in disability.
  • One of the participants died and another required intensive hospital care for liver complications. All participants developed fevers, which were frequently associated with infections, and other toxicities.
  • Additional research is focusing on figuring out who might benefit from this procedure and how to reduce its risks.

“These results suggest that aggressive MS may be stopped with an effective but risky procedure, for a subset of people,” said Dr. Bruce Bebo, Executive Vice President, Research, at the National MS Society. “Additional research by investigators around the world is focusing on figuring out who might benefit from this procedure and how to reduce its risks, which can include death.”

Details
Background: An experimental procedure that has been explored for several years in MS is called “autologous hematopoietic (blood cell-producing) stem cell transplantation” – or HSCT. This procedure has been used in attempts to “reboot” the immune system, which launches attacks on the brain and spinal cord in people with MS.

In HSCT, the stem cells (derived from a person’s own bone marrow or blood) are stored, and the rest of the individual’s immune cells are depleted by chemotherapy. Then the stored stem cells are reintroduced by infusion into the vein. The new stem cells migrate to the bone marrow and over time produce new blood cells, including immune cells. The goal of this currently experimental procedure is to establish a new immune system that no longer recognizes myelin and other nervous system tissue as dangerous. In theory, this should stop the attacks that lead to tissue damage and disability.

There are a number of laboratories around the world testing variations of HSCT for the treatment of autoimmune diseases, including MS. Preliminary findings suggest this is a promising, but potentially risky strategy for the treatment of MS.

The Study: Drs. Harold Atkins, Mark Freedman and team at the Ottawa Hospital, University of Ottawa and other institutions in Canada conducted a Phase 2 trial of HSCT that involved 24 people with aggressive relapsing-remitting MS whose disease was not controlled with available therapies. No control group was used which would have enabled comparison against the results found in the treatment group. The procedure used by this group included complete destruction of bone marrow cells and an additional step that enriched the transplanted cells for stem cells.

Results – Safety: One of the participants died of transplantation-related complications that caused liver failure and another required intensive hospital care for liver complications. The treatment regimen was modified over the course of the study to reduce toxicity, but all participants still developed fevers, which were frequently associated with infections.

Results – Effectiveness: Three years after the procedure, 70% of the participants remained free of disease activity, meaning they had no relapses, no new MRI-detected inflammatory brain lesions, and no signs of progression. The remaining 30% experienced progression of disability. In addition, for the entire follow-up period ranging from 4 to 13 years after the procedure, of the 23 survivors:

  • None experienced clinical relapse, had new active inflammatory MRI brain lesions, or required MS disease-modifying therapies to control their disease.
  • The average rate of brain atrophy (shrinkage), a measure that has been linked to MS progression, returned to levels associated with normal aging.
  • 40 percent experienced some lasting reversal of disability such as vision loss, muscle weakness and balance problems.
  • Some were able to return to work or school.

The results were published online on June 9, 2016 in The Lancet.  Major funding for the study came from the MS Society of Canada and its affiliated Multiple Sclerosis Scientific Research Foundation.

Next Steps: Rigorous clinical trials of stem cell therapies are needed to determine their safety and effectiveness in people with MS. Trials of this and other stem cell therapy approaches are taking place in Canada, the United States, Europe and elsewhere. To help explore the potential of stem cell therapy, in November 2015, the International Conference on Cell-Based Therapy for Multiple Sclerosis was convened in Lisbon, Portugal under the auspices of the International Advisory Committee on Clinical Trials in MS (a group jointly sponsored by the National MS Society and the European Committee for Treatment and Research in Multiple Sclerosis). Seventy leading researchers and clinicians conferred on clinical trials needed to provide answers about which types of cells, which route of delivery, and which types and stages of disease, would be the most promising approach for treating MS. Read more about this meeting

Read more about stem cells and MS

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