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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.”

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Study suggests antibody may have therapeutic effect on MS

Researchers have developed an antibody with potential therapeutic effects against multiple sclerosis. The discovery opens up a new strategy for controlling the disease.

For the cells of the immune system circulating in the bloodstream to reach the central nervous system, they must penetrate the blood-brain barrier and blood-spinal cord barrier. During previous work, the authors studied a factor involved in opening the blood-brain barrier, the NMDA receptor. They found that blocking the interaction of this receptor with tPA has beneficial effects linked with maintaining the integrity of the barrier.

Scientists at the Institut National de la Santé et de la Recherche Médicale, in France, developed a monoclonal antibody (Glunomab) directed against the specific site on the NMDA receptor to which tPA binds. In cellular models of the human blood-brain and blood-spinal cord barriers, the use of this antibody prevented opening of the barrier under inflammatory conditions, limiting the entry of lymphocytes. The team then tested the therapeutic effects of the antibody in an experimental mouse model of MS. After intravenous injection of Glunomab, the progression of partial or total paralysis of the limbs – as assessed by a clinical score – was blocked. In these treated mice, this effect was linked with reduced infiltration of lymphocytes into the nervous tissue, and reduced demyelination.

Results of mouse model studies sometimes do not translate to humans and may be years away from being a marketable treatment. However, the authors argue that by preventing myelin destruction by the cells of the immune system, this strategy might represent a promising therapy for the control of MS.

The study was published in the journal Brain.

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

Canadian Researchers Uncover Rare Gene that Increases Risk of Progressive MS

Researchers at the University of British Columbia have uncovered a rare gene mutation that appears to dramatically increase the risk, in some individuals, of developing a severe form of progressive multiple sclerosis. While the cause of MS is not known, scientists believe several different factors, including susceptibility genes, may interact to trigger the disease. The gene was discovered in two unrelated families that had multiple members with MS. The researchers also determined that the gene (NR1H3) contains instructions for a protein called LXRA, which is thought to be a control switch for genes involved in many functions, including some that help control inflammation and integrity of nerve-insulating myelin in the brain and spinal cord. This type of discovery can provide crucial clues to biological pathways that underlie MS, and may lead to new approaches for stopping MS and restoring function. The study, by Drs. Carles Vilariño-Güell, Weihong Song, A. Dessa Sadovnick and others, was funded in part by the MS Society of Canada and appeared in the journal Neuron on June 1, 2016.

The Latest on Stem Cell Treatment

Recent media reports have featured news about a clinical trial involving harvesting a person’s own stem cells to treat aggressive multiple sclerosis.
• This treatment, called autologous haematopoietic stem cell transplant (HSCT), attempts to “reboot” the immune system, which is believed to launch attacks on the brain and spinal cord in people with MS.
• HSCT is under investigation in clinical trials in Canada, the United States, Europe and elsewhere. Clinical trials are needed to fully understand the benefits and risks of HSCT in MS, and who might benefit most from this approach, since it does not seem to be effective in all types of MS.
• In HSCT, stem cells from a person’s own bone marrow or blood are stored, and the rest of the individual’s immune cells are depleted usually by chemotherapy. Then the stored stem cells are reintroduced and over time they produce new cells that repopulate the body with immune cells.
• There is exciting progress being made through innovative research related to the potential of many types of stem cells both for slowing MS disease activity and for repairing damage to the nervous system.
• At present, there are no approved stem cell therapies for MS. Stem cell therapy is in the experimental stage, and it’s important for people to have the best available information to understand this exciting area of research and make decisions related to this complex issue.
• In November 2015, the International Conference on Cell-Based Therapy for Multiple Sclerosis was convened by the National MS Society and the European Committee for Treatment and Research in Multiple Sclerosis, bringing leading researchers and clinicians together to confer 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. A summary and consensus on next steps will be published by the conference organizers, with recommendations to help speed the development of new cell-based treatment solutions.
• With the urgent need for more effective treatments for MS, particularly for those with more progressive forms of the disease, we believe that the potential of all types of cell therapies must be explored. The Society is currently supporting 12 research projects exploring various types of stem cells, including cells derived from bone marrow, fat and skin, and has supported 68 stem cell studies over the past 10 years.

Small Pilot Trial Suggests High-Dose Vitamin D is Safe and Regulates Immune Responses in People with MS

Summary
• High-dose vitamin D supplementation increased vitamin D levels in the blood, was safe and tolerable, and reduced the proportion of immune cells that are thought to drive disease, in a small study of 40 people with relapsing-remitting MS.
• The trial was too small to detect differences in disease activity, but a larger Society sponsored trial of vitamin D supplementation is currently recruiting participants.
• The team (Elias S. Sotirchos, MD, Pavan Bhargava, MD, Peter A. Calabresi, MD, and colleagues, Johns Hopkins University School of Medicine, Baltimore) has published results in Neurology. Dr. Bhargava was funded by a Sylvia Lawry Physician Fellowship from the National MS Society.

Background: Multiple sclerosis involves immune attacks on the brain and spinal cord. A number of genetic and environmental factors influence whether a person will develop MS. These factors may also impact the severity of the disease. There is growing scientific evidence that low levels of vitamin D in the blood are a risk factor for developing MS. In lab mice, vitamin D can reduce the effects of EAE, an MS-like disease, and some evidence suggests it may impact ongoing disease activity in people who have MS.

An important initial step to pursuing this lead was to determine whether taking large doses of vitamin D was safe and provides any hints of impact against the immune activity that is associated with MS. A team at Johns Hopkins University undertook this preliminary step to determine whether a larger-scale clinical trial was warranted.

The Study: Investigators randomly assigned 40 people with MS to receive either 800 IU of vitamin D, or 10,400 IU, daily for six months (nutritional supplementation is typically 600 IU). Participants were maintained on standard disease modifying treatment throughout the course of the study. Blood tests were done at three and six months to determine whether the dose increased the levels of vitamin D in the blood, and immune system effects. Blood and urine were assessed for calcium levels, since an excess of calcium can be a side effect of high-dose vitamin D supplementation. The primary goals of this study were to determine safety and effects on immune activity markers.

The investigators reported a few adverse events that did not differ between the groups, and they were all minor.

Vitamin D levels increased more in the high-dose group, to a level that has been suggested as the optimal target for people with MS. Immune cells known as Th17 cells – which have been suggested to be major players in the immune attack on the brain and spinal cord in MS – were reduced in the high-dose group, but not in the low-dose group. Investigators also found that the higher the levels of vitamin D in the blood, the greater the reduction of Th17 cells.

Results were published in Neurology (published early online, December 30, 2015).

Next Steps: This team is now conducting a larger trial at several centers nationwide, in which they are recruiting 172 people with relapsing-remitting MS to compare the effectiveness of 600 IU of vitamin D supplementation versus 5000 IU vitamin D supplementation at reducing MS disease activity, when added to standard therapy with glatiramer acetate (Copaxone®, Teva Pharmaceutical Industries). The study is funded by a research grant from the National MS Society, with support from the Society’s Greater Delaware Valley Chapter.

Further research in the laboratory also is suggesting that vitamin D’s capabilities go beyond immune regulation. Read more

Read more about the larger, ongoing study
Read more about research on vitamin D and MS

New Study Suggests People with MS are at Increased Risk for Depression, Anxiety and other Psychiatric Disorders

Summary
• A large-scale study from Canada suggests that people with MS have increased rates of anxiety, bipolar disorder, depression, and schizophrenia compared to people without MS.
• Among people with MS, women were more likely than men to develop depression, anxiety disorder, and bipolar disorder, while men were more likely than women to develop schizophrenia. Although women with MS were more likely to develop depression than men, men developed depression at a much higher rate compared to men without MS.
• This study provides new information about the risks of psychiatric disorders in people with MS. Recognizing and addressing issues related to mental and emotional health can greatly improve quality of life for individuals and families.
• The National MS Society is focusing a light on psychosocial issues and emotional health in MS as part of its commitment to drive research and programs in wellness.
• The team (Ruth Ann Marrie, MD, PhD) published their results in Neurology (2015;85:1–8).
Details
Background: In scientific terms, having two chronic medical conditions at once is called “comorbidity.” There is growing recognition that comorbidities may complicate the diagnosis of MS and also influence disease progression, as well as an individual’s wellness and quality of life. It has long been known that depression and bipolar disorder are more common among people with MS than in the general population. In a recent study from Dr. Marrie and others, psychiatric disorders (depression and anxiety) were among the five most prevalent disorders occurring alongside MS. The current study specifically looks at psychiatric comorbidities in people with MS.

The Study: The team identified 44,452 persons with MS and 220,849 controls without the disease in administrative medical data from four Canadian provinces. They examined medical records to determine the incidence (new cases) and prevalence (all existing cases) of depression, anxiety, bipolar disorder, and schizophrenia from 1995 to 2005 among these groups.

The results show that the incidence and prevalence of anxiety, bipolar disorder, depression, and schizophrenia were all higher in people with MS than in people without MS in the control population. Among people with MS, women were more likely than men to develop depression, anxiety disorder, and bipolar disorder, while men were more likely than women to develop schizophrenia. Although women with MS were more likely to develop depression than men, men developed depression at a much higher rate compared to men without MS.

Results were published in Neurology (2015;85:1–8).

Next Steps: This study adds to a growing body of evidence on conditions that occur alongside MS. The National MS Society is focusing increased attention on psychosocial conditions in MS as part of its commitment to drive research and programs in wellness. Read more

In the face of a chronic, often progressive illness like MS, people may tend to focus primarily on their physical health and neglect their emotional health — which is an essential component of overall health and wellness. Recognizing and addressing issues related to mental and emotional health can greatly improve quality of life for individuals and families. Read more about emotional health and MS

New Lab Studies Add Evidence That High Salt Diets Increase Inflammation and May Have Implications for MS

Summary
• The results from two recently published laboratory studies suggest that high levels of salt shift the balance of the immune system toward inflammation, and that salt alters the function of several types of immune cells pertinent to MS.
• These two studies, which were both published in the Journal of Clinical Investigation, were led by Dr. David Hafler (Yale University) and Dr. Dominik Müller (Max-Delbruck Center, Berlin, Germany).
• Dr. Hafler is funded by the National MS Society to study the impact of high salt on the immune system, and the Yale team is also conducting a pilot clinical trial to explore the impact of high- and low-salt diets on MS disease activity.

Background: Eating high levels of salt, which is part of the typical Western diet, has been linked to heart disease, chronic inflammation, and cancer. Recent lab reports have also suggested that dietary salt can speed the development of the immune attack in an MS-like disease in mice, and that the mouse disease responds differently to salt depending on the gender and genetic makeup of the mice. One small study in people found a possible link between dietary salt levels and relapses in people with MS, but this study suggested a link, which is not the same as establishing an actual cause. So far, laboratory findings related to the effects of salt have been stronger than the few studies that have been reported in people. Understanding whether high dietary salt is a risk factor for developing MS or for worsening disease activity is an active area of research.

The Studies: Two studies recently published in the Journal of Clinical Investigation suggest that high dietary salt affects two types of immune cells in a way that increases inflammation, a state that is generally considered harmful in MS. A study by National MS Society-supported researchers at Yale University and Harvard Medical School led by David Hafler, MD, investigated the effects of high salt on regulatory immune cells called “Tregs.” Tregs normally suppress immune responses by other immune cells, but in people with MS Tregs have been shown to be less able to perform this helpful function to turn off attacks. The team showed in mice and in cells in lab dishes that high salt blocks the ability of Tregs to suppress potentially harmful immune cells, and shifts Tregs toward activity that increases inflammation.

The other study, by an international team led by Dominik N. Müller at the Max-Delbruck Center in Berlin, Germany, investigated immune cells called “macrophages.” This study showed that high salt blocks the activation of a subset of macrophages, reducing their ability to suppress inflammatory cells and creating an imbalance in the immune system. In mouse models, high salt diets also delayed wound healing.

Comment: Taken together, these laboratory studies add new evidence that high levels of dietary salt may increase inflammation and autoimmunity, and decrease the ability of regulatory cells and processes to limit harmful immune cell activity. More studies are needed to determine the possible role of a high-salt diet in the risk of developing MS and whether reducing salt intake may be helpful for reducing disease activity in people with MS. Dr. Hafler is funded by the National MS Society to study the impact of high salt on the immune system, and the Yale team is also conducting a pilot clinical trial to explore the impact of high- and low-salt diets on MS disease activity.

Read more about dietary factors that may play a role in MS
Read more about research on the immune system in MS

Study Uncovers Gene Variation Linked to Response to MS Therapy; May Open Up New Treatment Approaches

Collaborating researchers in the U.S. and Italy have uncovered a gene variant that appears to influence whether a person responds well to interferon beta, a commonly used therapy for relapsing forms of MS. More broadly, the gene may regulate immune activity in unexpected ways, and its discovery may lead to new approaches to stopping inflammation and immune attacks in MS. Drs. Federica Esposito and Filippo Martinelli Boneschi (San Raffaele Scientific Institute, Milan), Philip L. De Jager (Brigham and Women’s Hospital, Boston) and colleagues have published their results in the Annals of Neurology (Early online May 14, 2015). The study was supported by the National MS Society and several other agencies.

Background: For reasons that are unclear, some people with relapsing forms of MS do not respond well to therapy and continue to experience disease activity despite being on a disease-modifying therapy. Previous genetic studies in MS have uncovered over 159 genetic variations that contribute to making people susceptible to developing MS, but these studies haven’t identified genetic variations that influence how a person responds to treatment. Finding a way to identify early in the disease course the best therapy for an individual – a “personalized medicine” approach – is likely to improve outcomes of treatment and quality of life for people living with MS. One of the lead authors of this study, Dr. De Jager, recently won the Barancik Prize for Innovation in MS Research for tackling critical questions like this with the goal of developing personalized treatments and prevention of MS.

This Study: Trying a different approach to search for genetic influences on treatment responses, the investigators first studied a group of individuals with MS who were taking interferon beta or glatiramer acetate. The individuals were classified as being responders, partial responders, or non-responders to their medication based on specific criteria. Then the researchers analyzed their full complement of genes (genome-wide association study) and found one genetic variant that was consistently associated with lack of response to interferon beta. When the researchers repeated this in three other groups of people with MS from Italy, France and the U.S., this finding held up.

The genetic variant (rs9828519) is near a gene (SLC9A9) that controls pH levels (acidity) within cells. The team explored functions of this gene, and found that its activity was diminished in people more likely to have MS relapses. They also conducted laboratory work, finding suggestions that the gene appears to play a role in regulating immune cell activity, and that its loss leads to damaging immune reactions. This suggests the gene may play a broader role in regulating immune activity.

Comment: Although the results of this study are not yet ready for applying to the management of MS, this discovery may lead to new approaches for stopping inflammation and immune attacks in MS. In addition, this study is an important step toward the goal of personalized medicine. The researchers point out that additional research is warranted to confirm their findings and to determine whether the genetic variant is relevant to how well people respond to other MS medications.

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