MS Research Update 2008
A comprehensive overview of the six FDA-approved disease-modifying therapies used to slow MS activity, along with initial findings on many experimental treatments presently being studied for the treatment of MS.
Written by Dr. Diana M. Schneider
Based on the positive response to the "MS Research Update" that appeared in the Summer 2007 issue of The Motivator, this article incorporates advances and new information about the six Food and Drug Administration (FDA)-approved disease-modifying therapies (DMTs), as well as experimental drugs currently being studied for the treatment of MS. Below each listed medication are several highlights about the drug and related research. This is not a complete list and not all studies and their results are included. Please note that, in many instances, initial study results should be considered as preliminary, as additional studies and/or evaluations are needed before these findings may be confirmed.
The information provided 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 meetings dedicated to neurologic conditions and multiple sclerosis (MS). These include 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).
While many readers of The Motivator are well-versed in MS terminology and disease pathology, a listing of basic MS terms may be found along the right-hand side of this article. For additional information, readers may refer to the Health and Wellness column from the Summer 2007 issue of The Motivator. This column gives an overview of MS terminology, evaluative procedures, clinical trials, and treatments. To request a copy, please contact MSAA by calling (800) 532-7667. It may also be viewed online at www.mymsaa.org/publications/
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 regimen. Additionally, this article does not include medications for managing the symptoms of MS. Treatments for symptom management will be the subject of an article in an upcoming issue of The Motivator.
FDA-Approved Medications for the Treatment of MS
Experimental Oral Medications for the Treatment of MS
Experimental Monoclonal Antibody Medications for the Treatment of MS
Other Therapies Being Studied for the Treatment of MS
New Directions in MS Research
Early treatment with one of the approved disease-modifying therapies (DMTs) is now recommended to be considered by all individuals with the relapsing forms of MS. This is a result of the many studies confirming clinical observations that people on the ABCR drugs – Avonex, Betaseron, Copaxone, and Rebif – have had less disability, a lower annual relapse rate, reductions in the number and size of active lesions in the brain as shown on magnetic resonance imaging (MRI) scans, and a higher employment rate than individuals who have remained untreated.
There is also strong evidence that early treatment of a single event suggestive of MS can slow progression to clinically defined disease.
Therapies for the progressive forms of MS still lag behind these outstanding results for treating relapsing forms of MS, but research is now focused on a number of potential strategies for managing these more difficult, progressive types of the disease.
As the six Food and Drug Administration (FDA)-approved drugs for the treatment of disease progression have now been in use for some time, research and clinical trials are taking several new and exciting directions. These include:
Anyone interested in additional information about the clinical trials discussed here, or anyone interested in participating in a clinical trial, may visit www.clinicaltrials.gov. This website is a service of the United States National Institutes of Health, developed by the National Library of Medicine. The National Multiple Sclerosis Society also has a downloadable file containing information on clinical trials, which may be accessed at: www.nationalmssociety.org/research/clinical-trials/index.aspx.
Environmental Factors and Genetic Studies
Environmental factors include the long-known statistic that by percentage of population, the frequency of MS increases as one resides farther from the equator, with some exceptions. This trend may possibly relate to factors such as diet and fish oil, reduced exposure to sunshine and vitamin D deficiency, lifestyle, and other environmental issues.
A viral component may play an important role as well. Individuals infected with the Epstein-Barr virus (EBV) may be at an increased risk of developing MS, with a possibly greater risk for those with a history of mononucleosis (a manifestation of EBV infection). EBV is a leading candidate for environmental exposure that increases the risk of MS.
MS also has a significant genetic component, although it has been difficult to assess the nature of MS inheritance because of the relationship with one's environment. Researchers are now able to identify specific DNA sequences that appear to be associated with the risk of MS.
Researchers recently found genetic differences in individuals who respond to interferon-beta treatment and those who do not respond to the drug. In a study of 287 people with relapsing-remitting MS (RRMS), researchers identified 18 genetic variations, some of which were in regions of the genes that code for proteins that might logically be involved in the way that the interferons work. Larger studies are needed, but this is a step toward being able to predict who will respond to specific therapies for MS.
African-Americans tend to have a more aggressive disease progression than Caucasians, and they are more likely to have mobility impairments and symptoms that affect the optic nerves and spinal cord. Recent studies also indicate that African-Americans may be less responsive to interferon-beta treatment, although the potentially differing disease course may be at least partially responsible for this effect.
New Therapies under Investigation
The preceding overview 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: Some drugs, such as several antiepileptic drugs (lamotrigine [Lomictal ®], topiramate [Topamax®], and phenytoin [Dilantin®]); riluzole (Rilutek®), a drug used to slow the progression of amyotrophic lateral sclerosis; and brain-derived neurotrophic factor (BDNF) are in trials for neuroprotection, meaning that they may prevent damage to nerve fibers and myelin. Many of the drugs that have neuroprotective activity appear to do so by blocking sodium channels, preventing the entry of calcium into nerve fibers and thus lessening damage, or by decreasing the toxicity of free radicals in the brain.
Stem-cell transplantation: High-dose immunosuppressive therapy followed by transplantation of the patient's own stem cells may induce sustained remission in autoimmune disease, and is being tested as a rescue therapy for MS, when very active disease continues while on DMT. Six-year follow-up data in a group of 26 patients with secondary-progressive MS (SPMS) or primary-progressive MS (PPMS) treated with high-dose immunosuppressive therapy followed by stem-cell transplantation shows that most patients remain stable. The therapy may be more successful in early stages of the disease. A recent Phase II study in patients with RRMS suggest some neurologic improvement. Similar results have been obtained in a Brazilian study, in which the Expanded Disability Status Scale (EDSS) was stabilized or reduced in most patients and the number of new MRI lesions was reduced.
Antidepressants: A small study of fluoxetine (Prozac®) showed immunomodulating and neuroprotective effects that included a decrease of inflammation and blockage of sodium channels. Small early studies also showed a decrease in new lesions. A Phase II completed study of rolipram, an antidepressant with immunomodulatory activity, focused on tolerability, safety, and MRI changes.
Sex hormones: Estriol is an estrogen-like hormone that may have both neuroprotective and anti-inflammatory properties. A small pilot study with 10 non-pregnant women showed a significant reduction in inflammatory lesions as well as cognitive improvement. Based on these results, seven medical centers in the United States are conducting a two-year trial, enrolling 130 women with RRMS to receive daily Copaxone injections along with a daily estriol pill or a placebo. Additionally, a recent report of four women, whose MS symptoms remitted during infertility therapy, adds weight to the concept that sex hormones may be a viable anti-inflammatory therapy.
Parasites: There is some evidence 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. Studies are investigating whether controlled infection with helminths (a group of worms that infect the gastrointestinal [GI] tract worldwide) will decrease the number of new gadolinium-enhancing lesions on MRI and increase the number of specific types of T cells; secondary measures will include the percentages of other types of T and B cells. (The parasites will be eradicated after 48 weeks.)
Other Agents in Early Stages of Testing for Use in MS
Mycophenolate mofetil (CellCept®) is an oral immunosuppressant medication used to prevent transplant rejection. In a study of 86 patients, there was a mild but statistically significant improvement in EDSS scores, although the timed 25-foot walk continued to worsen slowly during the study. The mild improvement that was observed suggests that the drug may have potential for the treatment of progressive forms of MS.
A small two-year study of cyclophosphamide (Cytoxan®) in nine patients with aggressive RRMS demonstrated that the drug was safe and well tolerated. There was a statistically significant reduction in disability as measured by EDSS and in the number of gadolinium-enhancing lesions. Several of the patients continued to experience these benefits throughout the study; others experienced clinical and/or MRI exacerbations. The researchers note that this regimen is worthy of further study and may be an alternative to bone-marrow transplantation.
A Phase II study of CDP323, an oral Tysabri-like drug, is currently recruiting participants. This oral medication has a shorter half-life than Tysabri, which means that the drug is removed from the body more rapidly (half-life refers to the amount of time needed for the body to eliminate half of an administered dose). This study will evaluate the safety, tolerability, and MRI effects of CDP323 as compared to placebo.
A number of other agents have shown some encouraging immunomodulatory effects, either in animals or humans, and are now being tested for possible future use in MS. These include: the plant hormone beta-sitosterol; the plant-derived antioxidant quercetin; RTL1000 (recombinant T-cell receptor ligand), a highly selective protein that binds to and inactivates T cells; CGP77116, a small protein similar to myelin basic protein (MBP), 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; flupirtin, a non-opioid analgesic drug that may have a neuroprotective effect; MK0812, which targets proteins known as chemokines that attract immune-system cells to areas of inflammation; atacicept, a drug that blocks the development of mature B cells and inhibits the survival of antibody-producing cells; and symadex, which inhibits a pathway involved in macrophage maturation.
In conclusion, the MS community continues to have much to look forward to in the coming years. The currently approved MS medications work well, and most have proven to be safe and well tolerated over the course of several years. Emerging immunomodulating therapies currently in trials may offer advantages such as more convenience, less frequent dosing, fewer side effects, and greater effectiveness. However, safety concerns must be addressed. Experimental drugs aimed at providing neuro-protection, may one day prevent the loss of function due to MS progression; while remyelinating agents, designed to repair damaged nerves, may one day offer a return of function to individuals with progressive forms of the disease. Everyone in the MS community looks forward to the time when these potential treatments and cures may become a reality.
|Last Updated on Monday, 25 March 2013 11:15|