MS Research Update 2014

Published in February 2014, this update is a comprehensive overview of research findings on the FDA-approved disease-modifying therapies, as well as many experimental treatments

Written by Stephen Krieger, MD with Diana Schneider, PhD
Includes material by Margaret M. McCormick, RN, BSN, MSCN
Reviewed by Jack Burks, MD
Edited by Susan Wells Courtney


Photo of Stephen Krieger, MD
Stephen Krieger, MD

This year’s expanded MS Research Update incorporates new information about the approved disease-modifying therapies (DMTs), as well as numerous experimental drugs currently under investigation for the long-term treatment of multiple sclerosis (MS). Highlights and recent research results are provided for each drug. Please note that symptom-management drugs are not included in this report.

This 2014 edition of MSAA’s MS Research Update is being printed as a stand-alone issue, reflecting the incredible diversity and scope of research progress in MS. There is nonetheless far too much ongoing research in MS therapeutics for all of it to be covered here. This is therefore not a complete list, and not all study results could be included.

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 the 2013 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).

The year 2013 marked the 20th anniversary of the United States Food and Drug Administration’s (FDA) approval of Betaseron®, the first disease-modifying therapy for MS, and the beginning of the MS-treatment era. This medicine, and other available medications that followed, continue to show effectiveness over the long term. Importantly, these medications have also demonstrated a proven long-term safety track record, which is crucial when considering that people with MS often require treatment for decades.

A recent review by Mark S. Freedman, MD, in the journal Neurology1, summarized the positive long-term data for Avonex®, Betaseron®, Extavia®, Rebif®, and Copaxone®. These are the five FDA-approved drugs given via self-injection for the long-term treatment of MS. All five drugs (given individually, not in combination) 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.

Female doctorPreferably, treatment is now often started when a person is diagnosed as having a clinically isolated syndrome (CIS). This 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. The use of MRI scans to identify lesions characteristic of MS has taken away the need to watch and wait for a second attack of MS in order to make this diagnosis. Numerous studies with multiple types of disease-modifying therapies (DMTs) have confirmed that early treatment at the time of CIS is beneficial in the long term.

Tysabri® is another important DMT option available for individuals with MS. Given via intravenous (IV) infusion, Tysabri is effective in reducing MS-disease activity, both in terms of relapses and lesions as seen on MRI scans. However, this medication does carry a small risk of a viral brain infection called PML (described on page 12), caused by the JC virus. A blood test to identify those who have been exposed to the JC virus, along with the recognition of other risk factors, allows clinicians to minimize this risk.

Three oral medications have been approved to treat MS in the past three years. 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.

September 2012 saw the FDA approval of the second oral DMT for relapsing forms of MS, Aubagio® (teriflunomide). As with all of the approved drugs for MS, information on this medication’s clinical trial results, efficacy, and safety will be discussed in the pages to follow. Aubagio uses an entirely different mechanism of action, and presents another oral option to treat relapsing forms of MS.

The FDA approved the third oral DMT in March 2013, called Tecfidera™ (dimethyl fumarate or DMF; formerly known as BG-12). The data leading to its approval for relapsing MS, as well as ongoing studies, are included in this update. As MSAA Chief Medical Officer Dr. Jack Burks explains, “With the FDA approval of Tecfidera, a pill taken twice daily, another first-line oral treatment option for people with relapsing forms of MS becomes available. The combination of robust effectiveness data with only transient side effects (consisting mainly of flushing and gastrointestinal symptoms) adds a valuable treatment to the list of options for patients and doctors to discuss.”

Another new medication given by infusion, Lemtrada® (alemtuzumab, formerly known as Campath), was initially denied FDA approval in December, 2013. The pharmaceutical company Genzyme plans to appeal this decision. Please see details on these and many other new and emerging therapies in the pages to follow. As therapies for progressive forms of MS remain a crucial unmet need, this Research Update highlights in bold those clinical trials that include or focus on primary- and secondary-progressive MS.

Individuals reading this update may also be interested in reading MSAA’s cover story from the Winter/Spring 2010 issue of The Motivator, titled “MS Process and Targets for Treatment.” This article may be easily accessed on MSAA’s website at and by selecting “The Motivator” and the year of the issue. Anyone interested in receiving a printed copy of the magazine may call MSAA at (800) 532-7667.

This 2014 edition of MSAA’s MS Research Update is dedicated to the memory of Diana M. Schneider, PhD, who passed away in September 2013. Dr. Schneider contributed mightily to the field of multiple sclerosis, using her extraordinary skills in writing and communication to disseminate advances in research and therapeutics to the MS community. This MS Research Update is written on the foundation that she herself wrote, and she is listed as a co-author again this year not merely symbolically, but because many of the words you will read are hers. This is but one of the many living testaments to her legacy of insight and MS education.

For more information on the specific symptoms of MS and treatments, please visit, go to “About MS,” and then select “Symptoms.” Please refer to the section titled “Trial Phases for Investigating Drugs and Treatments” for a description of each clinical trial phase and the role it plays to confirm a drug’s safety and effectiveness.

Please note that the authors have reported on the most recent study results available at the time of publication. While every effort has been made to provide meaningful, timely, and balanced information on each available agent, keeping the length of information equal for each medication is not possible. Please know that the different lengths of text should in no way be considered as favoritism toward any one product. Additionally, please note that references have only been cited for the newer study results.

Editor’s note: Initial study results from therapeutic agents under investigation should be considered as preliminary, since additional studies and/or evaluations may be needed to prove the safety and efficacy of these agents. 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

Administered via Self-Injection

Administered via Intravenous (IV) Infusion

Administered Orally

Experimental Medications

A New Interferon

Administered Orally

Monoclonal Antibody Medications

About Monoclonal Antibodies: Monoclonal antibodies are derived from cells that are identical (cloned from a single cell and then replicated). They are produced from animal tissue, most commonly laboratory mice. Humanized monoclonal antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibodies produced naturally in humans. Monoclonal antibodies are an important type of medication, as they can be specifically targeted to perform a particular action, which is desirable when trying to impact a complex structure like the immune system. The name of all monoclonal antibodies ends with “mab,” including natalizumab (Tysabri), which is already approved for MS. Several other monoclonal antibodies have shown promise in MS, and these are reviewed in this section.

Other Therapeutic Strategies

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. These very brief snapshots of highly technical concepts will warrant more in-depth explanations in the future, if pilot clinical trials are encouraging.

Anti-LINGO: LINGO-1 itself is a protein in the central nervous system whose role is to halt myelination and prevent the survival of neurons. The cells making up all organs in the body receive such “instructions” regarding when to grow and when to cease growing. Without these sorts of cellular “checks and balances,” tissues could grow without restraint, as seen in some malignancies. Anti-LINGO-1 (BIIB033) is an agent with potential remyelinative properties, after animal studies showed that it blocks this protein responsible for stopping the growth of myelin. It was sho-wn to promote spinal cord remyelination and axonal integrity in the animal model of MS (EAE).

The first trials of experimental anti-LINGO to stimulate myelin repair – human Phase I trials66, involving 64 healthy adult volunteers and 42 people with relapsing or secondary-progressive MS – have been completed. In these trials, intravenous doses of anti-LINGO were well tolerated, and there were no serious adverse events; headache was the most frequent adverse event reported. The authors concluded that the results support advancing this myelin repair strategy into a Phase II clinical trial. The first Phase II trial of anti-LINGO launched in 2013,67 recruiting patients with newly-diagnosed MS involving the visual pathways (optic neuritis) to evaluate its effect on remyelination.

A second, larger Phase II trial68 looking at this drug in combination with Avonex will recruit approximately 400 patients and examine the degree to which patients have an improvement in disability with anti-LINGO. Since this agent does not reduce relapses or prevent new MRI lesions, further studies with anti-LINGO, and other potential remyelination therapies, will need to utilize new endpoints such as this to prove efficacy. This includes measurements of recovery or improvement on physical, visual, cognitive, and other functional assessments of the effects of MS.

For a detailed review of the science behind anti-LINGO-1, please see the article in CNS Drugs, “Blocking LINGO-1 as a Therapy to Promote CNS Repair: From Concept to Clinic,” Mi et al, 2013.69

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, including one evaluating erythropoietin as an adjunct treatment for optic neuritis.70

Idebenone (Catena®, Sovrima®): This experimental drug, similar to coenzyme Q10, was initially developed to treat Alzheimer’s disease and other cognitive defects. Coenzyme Q10 is produced within your own body and is necessary for cells to grow and remain healthy. This substance also works as an antioxidant, helping to prevent injury from the oxidation process. 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. Oxidation is the body’s natural metabolism of oxygen. When disturbances occur in this process, “oxidative stress” can result, causing damage to the body’s cells and tissues. Oxidative stress is believed to be a contributing factor in many diseases, including those affecting the nerves and the immune system.

A double-blind, placebo-controlled Phase I/II clinical trial of idebenone71, 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 September 2016.

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. A Phase I/II study to evaluate the safety and tolerability of IV-administered MIS416 in people with either PPMS or SPMS presented interim results in 2012. This open-label, dose-escalation/ confirmation trial showed MIS416 to be well tolerated and identified a clinical dose for further evaluation. Moreover, during the dose confirmation portion of the study, eight of 10 patients with SPMS who were treated with MIS416 for 12 weeks showed some improvement. Further Phase II studies are planned, but are not as yet enrolling.

Transdermal Administration of Peptides: A small Polish study of 30 individuals72 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 Expanded Disability Status Scale (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 gadolinium-enhancing lesion volume and T2-lesion volume. The treatment was safe and well-tolerated. This approach may be pursued in future studies.

Other Agents in Development

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

Secukinumab (AIN457) is a humanized monoclonal antibody to IL-17. A preliminary study73 administered AIN457 to a very small number of patients with psoriasis, rheumatoid arthritis, and uveitis with variable results. A proof-of-concept trial in RRMS74 enrolled 73 patients and showed a reduction in gadolinium-enhancing MRI lesions compared with placebo.75 A larger, Phase II trial has been planned to enroll approximately 380 patients with relapsing MS; the design was presented at ECTRIMS in Fall 2013.

RTL1000 is a protein that inhibits the activation of myelin-reactive T cells, preventing the release of inflammatory cytokines and causing the release of anti-inflammatory cytokines. This molecule is related to the pathways studied transdermally (through the skin), as discussed earlier with peptides. A preliminary safety/tolerability dose-finding study of RTL1000 was reported in 2012.76

SB-683699 (firategrast) is an oral agent thought to reduce the number of active white blood cells entering the brain via a similar mechanism to Tysabri. It had positive results in a placebo-controlled Phase II trial77 using gadolinium-enhancing lesions as the primary outcome.

New Directions in MS Research

Closing Notes

Photo of a doctor and patient sitting at a deskIn 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 personalize the decisions about MS therapy in a precise, biologically-driven manner. And ongoing clinical trials in PPMS and SPMS, as well as investigations into neuroprotection, remyelination, and repair, offer great promise for the treatment of progressive MS and the goal of reversing the damage caused by this disease.

In recent years, our arsenal of MS therapies has grown considerably. Along with these new therapies comes a host of new challenges and risks, which will require vigilance and a thoughtful approach to medication selection and management. The new generation of MS medications will undoubtedly enhance both the benefits, and the complexity, of the MS therapy decision-making process.

As clinicians have more numerous and more complex treatment options to offer patients, the need for patient education and awareness has become more crucial. Now more than ever is the age of empowered, highly-informed patients, who can be true participants in their MS care in collaboration with their treatment team. We hope this update is a valuable part of that process. For more information about clinical trials, please visit For more information about MS and its treatments, please contact MSAA at (800) 532-7667, or visit