MSAA: Publications - The Motivator: Summer/Fall 2010 - Cover Story - MULTIPLE SCLEROSIS RESEARCH UPDATE
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Home > MSAA Publications > The Motivator > The Motivator: Summer/Fall 2010 > Cover Story - MULTIPLE SCLEROSIS RESEARCH UPDATE
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A comprehensive overview of the eight FDA-approved disease-modifying therapies used to slow MS activity (including the newly approved oral therapy, Gilenya), and initial findings on many of the experimental treatments in development for the treatment of MS.

By Diana M. Schneider, PhD and Jack Burks, MD
Edited by Susan Wells Courtney

Based on the positive response to the "MS Research Updates" published from 2007 through 2009 in New England Journal of Medicine, 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 treatment of MS. Highlights and recent study results are provided for each drug. This is not a complete list and not all information is included. Initial findings should be considered as preliminary, as 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 annual conferences of the American Academy of Neurology (AAN), the Consortium of Multiple Sclerosis Centers (CMSC), and the Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS and ECTRIMS).

This has been an especially active year both for new studies on existing drugs, with increasing data that help improve their usage, and for new and upcoming therapies. A great deal of excitement surrounds a sizable number of oral agents, which show promising results based on earlier Phase II studies. Five of these oral agents are now being tested in Phase III studies. The data from Phase III studies of two of these oral agents, Gilenya (fingolimod) and cladribine, were published in the January 20, 2010 online version of the New England Journal of Medicine.

On September 21, 2010, while this issue of The Motivator was in production, the announcement was made that Gilenya (pronounced as "Jil-EN-ee-ah") was approved by the Food and Drug Administration (FDA). This is the first oral disease-modifying therapy available for the long-term treatment of MS. The approval of an oral DMT option is exciting news for members of the MS community.

Additionally, cladribine has been granted Fast Track approval and may be approved by the FDA in the first quarter of 2011. A third drug, oral laquinimod, has recently been granted Fast Track status as well. Oral teriflunomide and BG-12 (dimethyl fumarate) are also in phase III studies with the hopes of filing for FDA approval in the near future. All of these drugs are described in detail in the sections to follow.

A brief overview of MS terms and clinical trials is on page 38. 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." This may be found online at

Please note that this article does not include medications for managing the symptoms of MS. Treatments for symptom management are the subject of an article in the Winter/Spring 2009 issue of The Motivator. This may be found online at

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.

Lemtrada® (alemtuzumab, formerly Campath)

FDA-Approved Medications

Experimental Oral Medications

Experimental Monoclonal Antibody Medications

Other Therapies In Development


Predicting the Response to Treatment

Researchers continue to look for factors that may predict a positive or negative long-term outcome from a disease-modifying therapy. For example, a multi-center study of both mice with EAE (an MS-like condition in animals) and patients with RRMS showed that interferon-beta was effective in reducing EAE symptoms in disease induced by one type of T cells (T helper type 1), but that it exacerbated disease induced by another type of T cells (T helper 17 cells).

Effective treatment correlated with increases in interleukin-10 in the mice whose EAE was the result of the type 1 cells. In RRMS patients, non-responders to interferon-beta had higher interleukin-17 concentrations in their serum compared to responders. The researchers concluded that a high level of interleukin-17 in the serum of people with RRMS is associated with non-responsiveness to interferon-beta therapy.

Genetic differences also appear to exist between individuals who respond to interferon-beta treatment and those who do not. An Irish study which looks at how DNA relates to relapse rate and interferon treatment, and a German study which identifies the genes affected by interferon treatment, are noted in the following section.

Genetic Studies

A study from Ireland found that a slight variant in the DNA (single-nucleotide polymorphism) predicts how early a relapse may occur while on interferon-beta treatment. Potentially, this may help clinicians identify individuals who are less likely to respond to treatment.

In the spring of 2010, findings from a German study indicated that the function of 121 genes were altered by interferon beta-1a treatment, with 11 being especially prominent in terms of altering activity. This is a step toward eventually having the ability to predict which patients may or may not be expected to respond to a specific therapy.

Slight genetic variants may also explain why African-Americans tend to have a more aggressive disease progression than Caucasians and may be less responsive to interferon-beta treatment.

Australian researchers have discovered two new locations of genes that are linked to genetic susceptibility for MS. They also indicate a link between genetic susceptibility to MS and other autoimmune diseases, including Type 1 diabetes, rheumatoid arthritis, and Graves' disease (a thyroid disorder). The new gene locations also indicate the potential involvement of vitamin D metabolism (please see page 27).

New Therapies under Investigation

The earlier listing of approved and experimental drugs is only a fraction of the many treatments currently in development. 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 of a variety of cell types in the CNS, as well as to promote regeneration after MS-related damage has occurred, with the goal of preventing the development of disability. A variety of neuroprotective strategies are in the early stages of testing.

Some of the drugs thought to have neuroprotective activity appear to reduce damage by blocking sodium channels or by blocking the release of the damaging neurotransmitter glutamate. Some of these drugs may decrease the toxicity of free radicals in the brain. A number of research studies are ongoing on a wide variety of agents that may have neuroprotective effects. Some of these studies are discussed in previous sections on specific therapies.

A Phase II study now recruiting is designed to study the possible neuroprotective effect of lamotrigine and interferon beta-1a (Avonex given 30 mcg once weekly via intramuscular injection) in patients with RRMS. The study will focus on the safety of this combination.

An 18-month German study of sunphenon epigallocatechin-gallate (egcg) in patients with RRMS (SuniMS) is currently recruiting participants. Sunphenon is a green tea extract that contains 95-percent egcg. It will be given daily as an oral medication to determine whether it has anti-inflammatory and neuroprotective properties as assessed by MRI and clinical examination. Primary outcome measures include the number of new T2 lesions on an MRI of the brain; secondary outcome measures include the development of brain atrophy as well as safety and tolerability.

A Phase II study of flupirtine is still recruiting participants with RRMS. Flupirtine is a non-opioid analgesic drug that has been shown to have additional neuroprotective functions related to a reduction in the damaging glutamate neurotoxic pathway. The study began in December 2007 and has 80 participants; data collection will be completed in December 2010. Flupirtine is administered twice daily as an oral medication for a period of 12 months.

Neuroprotection is assessed by an MRI, magnetic resonance spectroscopy, optical coherence tomography, and clinical examination. The primary outcome measure is the cumulative number of new T2-hypertensive lesions on cranial magnetic resonance imaging. Secondary outcome measures include cerebral atrophy, the number of new and total gadolinium (Gd)-enhancing lesions, disease progression (as measured by the EDSS and MSFC), and retinal nerve fiber layer thickness, assessed by optical coherence tomography.

Bone-marrow derived, stem-cell transplantation: High-dose immunosuppressive therapy followed by transplantation of the patient's own bone-marrow-derived stem cells has been used to prevent transplant rejection for many years. Taken from one's own bone marrow, this is the same type of stem cell that has been used in most MS studies - not to be confused with embryonic or other types of stem cells. The procedure is being tested in MS when very active disease continues while on a disease-modifying therapy. Evidence to date suggests that the therapy may be more successful in early stages of the disease.

In a Phase I/II study of 21 individuals with RRMS whose disease had continued to progress despite treatment with interferon-beta, 17 showed improvement of at least one point on the EDSS scale. Five of the 21 relapsed but achieved remission after further immunosuppression. After 37 months, all patients were free from progression, and 16 were free of relapses. Significant improvement was also seen in symptoms such as balance, walking and weakness, as well as self-reported quality of life.

A Phase I safety study being initiated at the Cleveland Clinic involves first removing and storing bone marrow cells, which are restored to the marrow after the patient's immune system is suppressed. This study involves approximately 24 participants with relapsing forms of MS (approximately equal numbers with RRMS and SPMS) and evidence of involvement of the visual system.

Mesenchymal stem cells (MSC) are cells derived from tissues other than bone marrow. A small study of autologous (derived from a person's own body) MSC transplantation is not yet open for participant recruitment and will have 24 participants. It is scheduled for completion in December 2013. The primary outcome measure is to evaluate infusion-related safety and tolerability; the secondary outcome measure is the effects on MS disease activity as measured by the number of Gd-enhancing brain MRI lesions.

Early data from a Pilot Phase I/II clinical trial in Israel suggest that intrathecal and intravenous injection of MSC is a clinically feasible and relatively safe procedure. The trial used autologous mesenchymal stem cells in 15 patients with MS and 19 with ALS. With the MS patients, the mean EDSS score improved from 6.7 to 5.9 after six months. Further controlled studies and longer observation periods are needed to evaluate long-term safety and potential clinical efficacy.

A Phase III study of hematopoietic stem cell therapy with 110 participants began in January 2008 and is expected to be completed in January 2012. (Hematopoietic stem cells are derived from the bone marrow and give rise to all of the blood cell types.) Participants will be selected based on failure to respond to previous interferon treatment. The study is currently recruiting participants. The primary outcome measure is progression in the EDSS over four years.

Sex hormones: Estriol is an estrogen-like hormone that may have both neuroprotective and anti-inflammatory properties. Its possible use in MS was suggested by the fact that women with MS tend to have fewer relapses during pregnancy, but are often subject to relapses during the postpartum period, when the high levels of female steroid hormones present during pregnancy return to normal levels.

Parasites: Some evidence supports that infections such as gut parasites normally help to regulate immune activity, and that the increase in autoimmune diseases in industrialized countries may in part be an unintended consequence of improved hygiene. Ongoing studies selectively expose individuals with autoimmune disease, including MS, to these organisms.

As of August 2010, the Phase II study, "Helminth-induced Immunomodulation Therapy (HINT)," was recruiting 20 individuals with RRMS at the University of Wisconsin in Madison and the Marshfield Clinic. Participants will receive a dose of 2,500 ova (tiny eggs) in liquid form every two weeks. After this liquid is ingested, the eggs hatch and grow to the size of an eyelash within the digestive tract, but once in the large intestine, the body's immune system kills the larvae. The primary outcome measure is MS activity, as judged by the number of new gadolinium-enhancing lesions on serial MRI scans. The study is estimated to be completed in March 2011.

A Phase II study of CDP323 was recently discontinued due to a lack of significant changes in MRI findings and possibly other clinical measures in the study population. CDP323 is an oral Tysabri-like drug that has a short half-life, meaning that it is removed naturally from the body more rapidly than Tysabri. It had been hoped that the drug would have less risk for PML than Tysabri. The cancelled study was evaluating the safety, tolerability and MRI effects of CDP323 as compared to placebo. No cases of PML (progressive multifocal leukoencephalopathy) were noted.

RTL1000 (recombinant T-cell receptor ligand) is a highly selective protein that inhibits the activation of myelin-reactive T cells, preventing the release of inflammatory cytokines and causing the release of anti-inflammatory cytokines. Preliminary results of a Phase I trial of patients with RRMS and SPMS reported in the spring of 2010 indicated that IV infusion at a dose of 60 mg is well tolerated. Although this study was not designed to assess efficacy, immunological data in a subgroup of patients indicated RTL1000 had positive effects on MRI and clinical disease indicators.

BAF312 is an S1P receptor modulator, one of the same class of drugs as fingolimod, that has been shown to reverse EAE in mice. Once-daily oral application of BAF312 was initiated during established, chronic EAE. It was associated with a remission of severe neurological paralysis and improved motor function in mice. In the same setting, Gilenya (fingolimod, 3 mg/kg orally once daily) and Copaxone (2 mg/mouse subcutaneously once daily) induced a 61-percent and a 19-percent reduction of clinical scores, respectively.

CS-0777 is another S1P receptor modulator. It causes a transient, dose-dependent decrease in circulating lymphocytes and T and B cells.

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: CGP77116, which is a small protein similar to myelin basic protein (MBP) and designed to modify the immune reaction that destroys myelin; SB-683699, thought to reduce the number of active white blood cells entering the brain; RG2007, which may block a T-cell pathway involved in MS; CS-0777, an oral immunosuppressive drug in Phase I studies; MK0812, which targets proteins known as chemokines that attract immune-system cells to areas of inflammation; and symadex, which inhibits a pathway involved in macrophage maturation.

Atacicept (ATX-MS-1467) is a "cocktail" of four peptides derived from human myelin basic protein. It appears to block the development of mature B cells and inhibits the survival of antibody-producing cells. The drug is now in Phase II trials to evaluate its safety and tolerability, along with determining whether it reduces CNS inflammation in RRMS on MRI. It is administered via subcutaneous injection.

Anti-Lingo-1 (BIIB033) is a monoclonal antibody now being readied for its first human Phase I trial, and is presently enrolling participants. It will focus on safety and tolerability. The study started in January 2010 and is scheduled for completion in June 2011. The primary outcome of the study is to evaluate the safety and tolerability of a single dose of Anti-Lingo-1 given via IV infusion, administered to healthy adult volunteers. Previous animal studies showed that it promotes spinal cord remyelination and axonal integrity in the animal model of MS (EAE).

A small French study of masitinib, a drug which targets mast cells, was tested in 35 patients with either PPMS or SPMS. During 18 months of treatment, EDSS scores remained stable in both treated and placebo groups with PPMS. In the SPMS group, the treated individuals remained stable, while the placebo group averaged an increase of one EDSS point. This small population, "proof of concept" study (which refers to early studies, prior to phase III) suggests that targeting mast cells might provide a therapeutic option for both PPMS and SPMS patients. Data will give ground for a large-scale phase III trial.

MN-166 (ibudilast) is an orally administered small molecule with neuroprotective and anti-inflammatory properties. In the first year of a two-year study in individuals with RRMS, it significantly reduced the percentage of brain volume loss and prolonged time to first relapse by 157 days. It did not, however, significantly reduce cumulative new lesion count, which was the primary outcome measure of the study.

A Phase II study to evaluate the effectiveness of oral recombinant ovine interferon tau in RRMS indicated effectiveness in decreasing the number of new gadolinium-enhancing lesions during a nine-month period. It also appeared to be both safe and well-tolerated.

Closing Notes

In summary, the future of disease-modifying therapies (DMTs) for MS looks bright, both in terms of new information on currently approved DMTs, as well as exciting results for emerging therapies. For approved therapies, studies will continue to evaluate long-term effectiveness and safety, as well as their possible usefulness in combination therapies. With new treatments, because of their complex mechanisms of action and potential side effects, weighing the benefits against possible risks is vital.

Research is ongoing into a wide variety of experimental therapies, including those that may be effective for individuals with the progressive types of MS, as well as those with relapsing disease who have not to date responded to any of the presently approved DMTs. Exciting new findings about the processes that underlay the development of MS and the mechanisms by which it produces nervous system damage are being made at an accelerated pace. The coming years should bring many promising advancements in the treatment of all types of MS.

As always, your personal healthcare professionals will be your best guides to making the right decision for you. The great news is that effective treatments are available for certain types of MS. If treatment is appropriate, as determined by your doctors, the keys to success are: (1) to start therapy early in the disease when it is the most effective in preventing the accumulation of nervous system damage; (2) to stay on therapy once you've begun; and (3) continue under the care of your medical team, to monitor your ongoing response to the disease-modifying therapy as well as any side effects.

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 12:30