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.

Erythropoietin: Erythropoietin is a hormone produced by the kidneys that promotes the formation of red blood cells in the bone marrow. It has shown neuro-protective 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.45

Idebenone (Catena®, Sovrima®): This experimental drug, similar to coenzyme Q10, 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. 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 idebenone46, 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 individuals47 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 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:

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), discussed earlier. A preliminary safety/tolerability dose-finding study of RTL1000 was reported in 2012.48

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 trial49 using gadolinium-enhancing lesions as the primary outcome.

AIN457 is a humanized monoclonal antibody to IL-17. A recent study50 administered AIN457 to a very small number of patients with psoriasis, rheumatoid arthritis, and uveitis with variable results. A Phase II trial in RRMS51 enrolled approximately 90 patients in 2012; data is forthcoming.

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

Anti-Lingo-1 (BIIB033) is an agent with potential remyelinative properties, after animal studies showed that it promotes spinal cord remyelination and axonal integrity in the animal model of MS (EAE). BIIB033 has completed its first Phase I trial in 42 MS patients in 2012; data is forthcoming.

New Therapeutic Approaches

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 MS-related 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-marrow-derived stem cells, from which white blood cells developed, and mesenchymal stem cells, which are derived from tissues other than bone marrow.


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. Many types of biomarkers are being researched in MS, and are likely to grow in importance in the coming years.

Although the term itself is relatively new, biomarkers have long been used in medicine. 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 concept of personalizing MS care has been implemented in a general way by the use of disease-modifying therapies based on someone’s clinical course – CIS, RRMS, SPMS, PRMS, or PPMS – categories that are entirely based on a patient’s clinical history. This approach has been refined as clinicians may recommend “more aggressive” therapies based on markers of disease severity (such as MRI lesions), as well as on demographic factors that may be concerning for a more difficult disease course.

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. We already utilize one type of blood test to help predict ongoing therapeutic response – neutralizing antibodies to the interferons and Tysabri. A major goal of biomarker studies is to be able to decide which patient is most likely to respond to which therapy before it is started, so the decision about which medication to start can be optimized.

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. Another 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. A genetic study, with results reported in 2012, looking at the response to Copaxone, also suggested that multiple genetic markers may predict a favorable response to this medication.

An additional use of biomarkers will be to predict and minimize the risk of medication-related adverse events. This approach has already proved effective for new infectious biomarkers, such as the development of a blood test for JC virus antibodies, to identify who is at greater or lesser PML risk when treated with Tysabri. Based on this blood test, selection of Tysabri can be more precisely personalized to maximize the benefit/risk ratio for this medication in practice. This type of biomarker strategy may also prove useful in predicting the risk on an individual basis of non-infectious adverse events to some of the investigational medicines reviewed.

A strong link exists 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:K

  • 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 with 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 more than 1,000 people with RRMS participating in the CombiRx study (described on page 11); this includes patients on interferon only, Copaxone only, or a combination of both. Samples of serum and white blood cells are being obtained from each patient prior to the study and at regular intervals thereafter.

Although Copaxone and Avonex did not differ greatly in their efficacy in the CombiRx trial, certainly both drugs work well for some people and less well for others. This study will identify biomarkers (genes and the proteins they encode) and link them to clinical- and MRI-based outcomes, 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. Based on these genetic biomarkers, likely best-responders to either form of therapy can be identified.

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 saw a major breakthrough 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.

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.

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 personalize the decisions about MS therapy in a precise, biologically-driven manner.

In the short term, our arsenal of MS therapies is poised to grow. Along with these new therapies come 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.



  1. You actually make it appear so easy with your presentation but I find this
    topic to be really one thing which I believe I would never understand.
    It kind of feels too complex and extremely extensive for
    me. I’m taking a look forward for your next submit, I will attempt to get the hold of it!

    1. Some of the stories are very detailed techniques for treatment and research, but others are aimed at patients and caregivers or family members. I try to mix the news so that every visitor select the ones you are interested in based on their complexity or interest.
      Thank you very much for writing and I hope the blog is helpful.
      Jesus Santiago.


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