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Home > MSAA Publications > The Motivator > The Motivator: Summer/Fall 2011 > Cover Story - MS Research Update 2011
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A comprehensive overview of the eight FDA-approved disease-modifying therapies used to slow MS activity, along with initial findings on many experimental treatments.

Written by Diana M. Schneider, PhD
Reviewed by
Jack Burks, MD
Edited by Susan Wells Courtney

Based on the positive response to the MS Research Updates published from 2007 through 2010 in The Motivator, this year's article incorporates new information about the eight approved disease-modifying therapies (DMTs), as well as numerous experimental drugs currently under investigation, for the long-term treatment of MS. Highlights and recent research results are provided for each drug. This is not a complete list and not all study results are included. Initial study results should be considered as preliminary, since additional studies and/or evaluations may be needed.

This information is based on a wide range of sources, including the extensive journal literature on MS and its management, a review of ongoing clinical trials, and papers presented at major national and international conferences. These include conferences hosted by the American Academy of Neurology (AAN), the Consortium of Multiple Sclerosis Centers (CMSC), and the American and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS and ECTRIMS).

Currently available medications continue to show effectiveness over the long term. A 2011 review by Mark S. Freedman, MD, in the journal Neurology, summarized the positive long-term data for Avonex®, Betaseron®, Extavia®, Rebif®, and Copaxone®. These drugs reduce the frequency and severity of relapses. They also show that long-term treatment improves outcomes by delaying the time to significant disease progression. In addition, treatment begun early in the disease process is correlated with optimal outcomes over the long term.

Preferably, treatment is now often started when a person is diagnosed as having a clinically isolated syndrome, or CIS. CIS is defined as a single attack (or the appearance of one or more symptoms characteristic of MS), with a very high risk of developing MS, when no other diseases or causes for symptoms are apparent.With today's MRI technology, it is no longer considered necessary to wait for a diagnosis of MS as "disseminated in space and time." This was a diagnosis made on clinical grounds alone, and required waiting until at least a second attack occurred before beginning treatment. The MRI findings can now be used as an adjunct to the clinical evaluation.

Recent studies with Tysabri® indicate that the drug may achieve a sustained improvement in disability for individuals with relapsing-remitting MS (RRMS). It substantially reduces clinical and MRI activity when other therapies fail. Progressive Multifocal Leukoencephalopathy (PML), an often-fatal viral infection of the brain, continues to be a concern. However, early diagnosis and treatment increases the survival rate to 80 percent (although often with disability). A blood test to determine those at greatest risk is currently under review by the Food and Drug Administration (FDA).

In September 2010, Gilenya® (fingolimod) became the first oral DMT approved by the FDA for the treatment of relapsing forms of MS. Studies show that it reduces disease activity and the progression of disability, while offering the advantages of an oral medication to individuals who have difficulty with the injected DMTs. Particularly when starting this treatment, and at regular intervals afterwards, patients are monitored for potential adverse events.

During the coming year, we anticipate that other new oral medications will be submitted for evaluation and potential approval by the FDA, including teriflunomide, laquinimod, and dimethyl fumarate (BG-12). One new injectible, Lemtrada® (alemtuzumab, formerly known as Campath and given via intravenous injection), may also enter or complete the approval process. Several more injectible drugs are also on the horizon, such as ocrelizumab, daclizumab, and Tovaxin®.

Please note that all articles noted below appeared in previous issues of The Motivator and may be easily accessed through MSAA's website at by selecting "Publications," "The Motivator," and the year for the issue.

A brief overview of MS terms and clinical trials is on page 38 of the Summer/Fall 2010 issue of The Motivator. For additional information, the "Health and Wellness" column from the Summer 2007 issue of The Motivator gives an overview of MS terminology, evaluative procedures, clinical trials, and treatments.

For an overview of the immune system in MS and how the disease-modifying therapies are thought to interrupt this process, please refer to the cover story from the Winter/Spring 2010 issue of The Motivator, titled, "MS Process and Targets for Treatment."

For more information (and earlier study results) on the approved and experimental drugs discussed in this article, please see previous "Research Updates" appearing in earlier Summer issues of The Motivator, from 2007 through 2010.

Please note that this article does not include medications for managing the symptoms of MS. Treatments for symptom management are the subject of the cover story in the Winter/Spring 2009 issue of The Motivator.

For those without internet access, please call MSAA at (800) 532-7667 to request a printed copy of any of the articles mentioned above.

Editor's note: MSAA does not endorse or recommend any specific products or therapies. Readers are advised to consult their physician before making any changes to their medication, diet, exercise, or other treatment regimen.

FDA-Approved Medications

Experimental Oral Medications

Experimental Monoclonal Antibody Medications

Other Therapies Being Studied

New Directions in MS Research


In medicine, the term biomarker refers to anything that can be used as an indicator of a particular disease state; in effect a biomarker is a surrogate for the disease state. It often refers to a protein measured in blood, whose concentration reflects the severity or presence of disease and/or that can be used to measure therapeutic effectiveness.

Although the term itself is relatively new, biomarkers have been used in medicine for many years. For example, body temperature is a well-known biomarker for fever, blood pressure helps determine the risk of stroke, and cholesterol levels are a biomarker and risk indicator for coronary and vascular disease. Biomarkers are often seen as the key to the future of what is termed personalized medicine. This refers to treatments that can be individually tailored to specific patients for highly efficient intervention in disease processes.

The search for biomarkers of MS is referred to throughout this article, and studies are ongoing for all major MS drugs to find markers that will help determine who should be treated with that drug as well as how effective the drug is after therapy is begun. The ultimate goal of these studies is to be able to decide which patient is most likely to respond to which drug, and then to follow him or her to see if the drug is working.

For example, current studies are showing that it may soon be possible to determine who might be a suboptimal responder to interferons, based on immune system-related substances that can be measured in the blood. A small study was designed to evaluate whether the type of cytokine present prior to treatment with Copaxone might act as a biomarker to identify those individuals with RRMS who are more likely to respond to immunomodulating treatments. It showed that people who responded to Copaxone secreted higher levels of specific inflammatory cytokines prior to treatment. The JC virus antibody test discussed earlier in the section on Tysabri is a good example of using a biomarker - the antibody - to indicate that the individual was previously exposed to this virus and may be more likely to develop PML.

There is a strong link between biomarkers and genetics, and the line between them may sometimes appear blurred. This is because many of the biomarkers that are being discovered relate to the activity of specific genes that code for proteins involved in inflammation, or are otherwise linked to the response to disease-modifying therapies. Studies of the gene expression signature, through global gene expression analysis, reveals the pattern of the entire DNA in an individual. This type of study has become possible due to recent advances in high-speed genetic pattern analysis. For example:

  • Genes found to be differently expressed in MS effectively become biomarkers for disease progression and may change as the result of treatment. A recent study identified several candidate genes that could potentially serve as biomarkers of interferon treatment or targets for therapeutic intervention in MS.
  • A study using gene expression analysis of whole blood showed significant differences in expression profiles of patients with optic neuritis compared with healthy controls.
  • Another study showed that interferon therapy induces the expression of genes involved in interferon regulation and signaling; a subgroup of patients who tended to have a higher risk for relapses showed a different expression of specific genes.

An ongoing clinical trial sponsored by the National Institutes of Health is studying 1,200 individuals with RRMS who are participating in the MS-CombiRx study; this includes patients on interferon only, Copaxone only, or a combination of both. Samples of serum and white blood cells will be obtained from each patient prior to the study and at regular intervals thereafter. This study will identify biomarkers (genes and proteins) and link them to clinicaland MRI-linked parameters, such as the extent of inflammation and rate of disease progression. It will examine how the biomarkers may be related to disease development and progression as well as differences among patients' symptoms and response to treatment.

Genetic Studies

As discussed in this article in previous years, there has been a growing body of evidence for the genetic component in MS. The studies on biomarkers have arisen as the result of this work, and a number of genes that are linked to the development of MS have been identified.

This field of research took a "giant leap forward" in August 2011, when the journal Nature published the results of the largest MS genetics study ever undertaken. A global collaboration of scientists identified 29 new genetic variants associated with MS, and confirmed 23 others that had been previously associated with the disease. The study confirmed that the immune system plays a major role in the development of MS: most of these genes are related to immune function, and more than one-third of them have previously been confirmed to be associated with other autoimmune diseases, such as Crohn's disease and type 1 diabetes.

The study involved nearly 10,000 people with MS and more than 17,000 controls without MS, in 15 countries. The research was carried out by approximately 250 investigators. The results are now to be confirmed and expanded in a second large-scale study.

The team found that a large number of these genes are related to T-cell function; they were mainly associated with T-cell activation and proliferation. This was particularly important because these are the cells believed to be the major mediators of the early immune attack on the brain and spinal cord in MS. Two of the genes are linked to Vitamin D, and low Vitamin D levels have already been implicated as a risk factor for developing MS. More than one third of the genes are known to be associated with autoimmune diseases such as Crohn's disease and type 1 diabetes; MS is believed to be an autoimmune disease as well.

The results of these and other genetics studies do not as yet significantly improve our ability to provide genetic counseling to individuals concerned about their risk of developing MS. However, they should help researchers to better define the biological pathways that lead to the development of MS. It is also hoped that they will enhance our ability to design better treatments for early MS.

New Therapies under Investigation

The earlier listing of approved and experimental drugs is only a fraction of the many treatments currently being studied. Some of the following are among the most exciting potential therapies under investigation.


Neuroprotective agents: The term "neuroprotection" refers to strategies designed to prevent irreversible damage from a variety of cell types in the central nervous system (CNS), as well as to promote regeneration after MSrelated damage has occurred. These have the goal of preventing the development of disability. A variety of neuroprotective strategies are now being studied.

One that seems especially promising is to identify the role that the neurotoxic transmitters glutamate and nitric oxide play in the development of neuronal damage, with the goal of preventing this process. At the same time, studies are focusing on stimulating growth factors that promote neural function, such as brain-derived neurotrophic factor (BDNF). This combination - decreasing factors that cause damage while at the same time increasing factors that stimulate growth - holds significant potential for preventing MS-related damage and stimulating neuronal function.

Bone-marrow derived, stem-cell transplantation: Based on encouraging results from a variety of studies, clinical trials are now starting to enroll patients. They involve both bone-marrowderived stem cells, from which white blood cells developed, and mesenchymal stem cells, which are derived from tissues other than bone marrow.


These very brief snapshots of highly technical concepts will warrant more in-depth explanations in the future, if pilot clinical trials are encouraging. More information on these drugs may be found on the Internet.

Cyclophosphamide (Cytoxan®): The use of highdose cyclophosphamide to treat progressive MS predates release of the first DMT in the early 1990s. Its toxicity has limited its use, and it is now used mostly as a "rescue therapy" for progressive disease that has not responded to more than one of the approved DMTs. Research on its use in progressive MS is still ongoing.

Erythropoietin: Erythropoietin is a hormone produced by the kidneys that promotes the formation of red blood cells in the bone marrow. It has shown neuroprotective effects in animal studies. A German Phase I/IIa pilot study suggests that high-dose treatment, but not a lower-dose regimen, leads to clinical improvement of motor function. Cognitive performance was also improved. Studies are ongoing.

Idebenone (Catena®, Sovrima®): This experimental drug was initially developed to treat Alzheimer's disease and other cognitive defects. It is being explored in MS because oxidative stress has been postulated to play a role in the death of myelin-producing cells, which has been linked to MS progression. A double-blind, placebo-controlled Phase I/II clinical trial of idebenone, sponsored by the National Institute of Neurological Disorders and Stroke, is currently recruiting participants with PPMS with little to moderate disability. It began in July 2009 and is scheduled for completion in May 2015.

MIS416: This "therapeutic vaccine" is a potent activator of the innate immune system, which provides immediate defense against infection but does not result in long-lasting or protective immunity. It has been primarily tested in cancer and acquired infections, with the goal of enhancing the inherent capability of a person's immune system to fight disease. An ongoing Phase I/II study will evaluate the safety and tolerability of IVadministered MIS416 in people with either PPMS or SPMS. Although this is primarily a safety study, effects on progression as measured by MRI and clinical status will be made at six months.

Masitinib: This drug targets mast cells, which are involved in allergic responses, wound healing, and defense against infection. It has been tested in a small group of patients and more data should be forthcoming in the next year.

MN-166 (ibudilast): This orally administered small molecule appears to have neuroprotective and anti-inflammatory properties.

Oral recombinant ovine interferon tau: This interferon decreased the number of new gadolinium-enhancing lesions during a ninemonth period in individuals with RRMS.

Transdermal Administration of Peptides: A small Polish study of 30 individuals with RRMS evaluated the efficacy and safety of transdermal (skin patch) administration of two dose levels of three myelin peptides: MBP 85-99, PLP 139-151 and MOG, versus controls. In the lower-dose group, which received 1 mg each of the three peptides, the annual relapse rate at one year was reduced by 65 percent compared with placebo, progression in the EDSS was slightly lower, and 56 percent were relapse-free versus 10 percent in the placebo group. The treated group also showed a decrease in gadoliniumenhancing lesion volume and T2-lesion volume. The treatment was safe and well-tolerated. This approach will be pursued in future studies.


A number of other agents have shown some encouraging immunomodulatory effects, either in animals or humans, and are under investigation for possible future use in MS. These include the following experimental treatments:

  • RTL1000 is a protein that inhibits the activation of myelin-reactive T cells, preventing the release of inflammatory cytokines and causing the release of antiinflammatory cytokines.

  • BAF312 and CS-0777 are S1P receptor modulators, in the same class of drugs as Gilenya. Both drugs are in ongoing preclinical studies. They cause a transient, dosedependent decrease in circulating lymphocytes (immune-system cells produced to fight infection and disease) and T and B cells.

  • CGP77116 is a small protein similar to myelin basic protein (MBP) and designed to modify the immune reaction that destroys myelin.

  • SB-683699 is thought to reduce the number of active white blood cells entering the brain.

  • RG2007 may block a T-cell pathway involved in MS.

  • MK0812 targets proteins known as chemokines that attract immune-system cells to areas of inflammation

  • Symadex inhibits a pathway involved in macrophage maturation.

  • Atacicept (ATX-MS-1467) is a "cocktail" of four peptides derived from human myelin basic protein that appears to block the development of mature B cells and inhibits the survival of antibody-producing cells.

  • Anti-Lingo-1 (BIIB033) is a monoclonal antibody now being readied for its first human Phase I trial; animal studies showed that it promotes spinal cord remyelination and axonal integrity in the animal model of MS (EAE).

Closing Notes

In summary, the future of disease-modifying therapies (DMTs) for MS continues to be promising, both in terms of new information about currently approved DMTs and exciting results for emerging therapies. Advances in genetic and biomarker studies hold the promise that, in the future, it will be possible to identify which patients should be treated with specific therapies, and to better evaluate their response to therapy.

As always, your personal healthcare professionals will be your best guides to making the right decision for you.

Anyone interested in additional information about the clinical trials discussed here, or anyone interested in participating in a clinical trial, may visit For more information about MS and its treatments, please contact MSAA at (800) 532-7667, or visit our website at


Last Updated on Monday, 25 March 2013 12:48