MS Research Update 2016

Written and compiled by Stephen Krieger, MD and Michelle Fabian, MD

Includes additional material by
Margaret M. McCormick, RN, BSN, MSCN
Reviewed by Jack Burks, MD
Edited by Susan Courtney

This year’s MS Research Update has been published jointly by the Multiple Sclerosis Association of America (MSAA), the Consortium of Multiple Sclerosis Centers (CMSC), and the International Organization of MS Nurses (IOMSN). MSAA greatly appreciates the support from the CMSC and IOMSN to assist with the production of this publication. The MS Research Update provides important new data on approved and experimental treatments for MS, and is a valuable resource to the entire MS community.

Please note that this update gives an overview of the research behind the approved and experimental medications and therapies for the long-term treatment of multiple sclerosis. It does not include information on any symptom-management medications or therapies. For additional information about MS, symptoms and symptom management, as well as MSAA’s programs and services, please visit or call (800) 532-7667. Questions to MSAA’s Client Services department may also be emailed to

Additionally, please note that due to the timing of the national and international MS conferences, study data from the 2016 conferences could not be included in this writing. Information in this publication includes data presented at the 2015 conferences, as well as any important updates that occurred in early 2016. Please visit MSAA’s website at for future summaries of 2016 conference highlights.

To learn about the Consortium of Multiple Sclerosis Centers (CMSC), please visit They may also be contacted via phone at (201) 487-1050 or via email at For information about the International Organization of MS Nurses (IOMSN), please visit


Photo of Co-authors Michelle Fabian, MD and Stephen Krieger, MD
Co-authors Michelle Fabian, MD and Stephen Krieger, MD

This year’s streamlined MS Research Update has been refined to emphasize numerous experimental drugs currently under investigation for the long-term treatment of multiple sclerosis (MS). Entirely new clinical trial data on some of the approved disease-modifying therapies (DMTs) has also been included. Please note that in order to keep this annual Research Update current and up to date, historical background and completed trials of approved DMTs are no longer included.

View a chart giving an overview of the approved DMTs.

This 2016 edition of MSAA’s MS Research Update is again 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 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 2015 conferences hosted by 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).

More than 20 years have passed since the United States Food and Drug Administration (FDA) approved Betaseron® (interferon beta-1b), the first disease-modifying therapy for MS, and the beginning of the MS-treatment era. The “watch and wait” approach to MS therapy has become a thing of the past, in favor of a proactive strategy to prevent MS-disease activity and disability.

Preferably, 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 expedited diagnosis. Numerous studies with multiple types of DMTs have confirmed that early treatment at the time of CIS is beneficial in the long term.

The past two years have seen the approval of a new formulation of Copaxone® (glatiramer acetate), dosed three times per week versus daily, as well as a new type of interferon called Plegridy® (peginterferon beta-1a), which is dosed once every two weeks. A new agent given by a series of infusions once yearly, Lemtrada® (alemtuzumab), was approved by the FDA at the end of 2014. With the success of research initiatives and the expanding number of approved medications, the choice of disease-modifying therapy has grown more complex.

In 2014, experts from member organizations of the Multiple Sclerosis Coalition (MSC), including the Multiple Sclerosis Association of America (MSAA), collaborated to develop and write a paper summarizing the current evidence that supports the FDA-approved DMTs for the long-term treatment of multiple sclerosis. The objectives were to provide evidence for the effectiveness of these medications and to provide support for broad access to these approved therapies for people with MS in the United States. Ultimately, the goal is to enable individuals with MS and their medical professionals to select the most appropriate medication available.

This professional paper, titled “The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence,” is available on MSAA’s website for anyone to review. It has been written expressly for medical professionals, in a highly detailed and scientific style. This paper for professionals may be accessed by going to

Following the release of the professional paper, member organizations of the MSC have collaborated to develop a summary, written in a more reader-friendly style to better serve the broader MS community. This paper is available on MSAA’s website as well and is titled, “The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence; SUMMARY.” This summary directly correlates to the different sections found within the professional version, but has simplified the information to highlight main points and incorporate more commonly used terminology. In addition, the summary is followed by an extensive glossary to assist with those terms specific to describing the MS process. This paper on the approved DMTs is a valuable counterpart to this Research Update, which is focused on summarizing new and emerging data covering available therapies as well as emerging treatments still in development. This paper for the MS community may be accessed by going to

Photo of two doctorsPlease 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 medication, 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, references have only been cited for the newer study results.

As symptom-management drugs do not fall under the scope of this report, for more information on the specific symptoms of MS and treatments for managing these symptoms, please visit and select “Symptoms” under “MS Information.” For information on trial phases, please refer to pages 38 and 39.

Readers may also note that studies involving progressive forms of MS are highlighted with the mention of progressive MS appearing in bold type. This is because all of the 13 presently approved DMTs are for relapsing forms of MS, and the authors of this publication want to also bring studies for progressive MS to the readers’ attention.

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

This MS Research Update 2016, covering information from the year 2015 and early 2016, must begin with a sobering note in regard to the failure of two highly anticipated clinical trials in progressive MS. By testing approved medications for relapsing MS in progressive disease, the possibility of extending the use of these well-known medications for progressive MS may be rigorously explored. Unfortunately, as discussed below, success in relapsing MS does not always predict similar efficacy in those with progressive disease. We begin with some of the unsuccessful studies of 2015 before moving on to the numerous positive avenues of ongoing MS research in both relapsing and progressive forms of MS.

New Data

Experimental Medications

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, again commonly a mouse, whose protein sequences have been modified to increase their similarity to antibodies produced naturally in humans. Monoclonal antibodies can be extremely powerful and effective, as they can be specifically directed toward a certain part of a system while leaving the other parts of the system untouched. This can be very desirable when trying to impact a structure as complex as the immune system. The name of all monoclonal antibodies ends with “mab,” including natalizumab (Tysabri) and alemtuzumab (Lemtrada), which are already approved for MS. Several other monoclonal antibodies have shown promise in MS, and these are reviewed in this section.

New S1P Receptor Modulators

Data have been presented on several investigational oral agents, now in ongoing clinical
trials, which have a mechanism similar to that of Gilenya, by isolating lymphocytes (that damage myelin) in the lymph nodes. These agents have been well-tolerated and reduced lesions related to RRMS. It is hoped that these agents, ozanimod (RPC1063), siponimod (BAF312), and ponesimod, will maintain or potentially improve on the efficacy and safety of Gilenya. However, researchers continue to remain vigilant with regard to cardiovascular side effects, such as bradycardia (slowed heart rate).

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 shown 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 trials,28 involving 64 healthy adult volunteers and 42 people with relapsing or secondary-progressive MS – have been completed. In these trials, intravenous (IV) doses of anti-LINGO were well tolerated, and there were no serious adverse events; headache was the most frequent adverse event reported.

The first Phase II trial of anti-LINGO, called RENEW, launched in 2013.29 The study recruited patients with newly-diagnosed MS involving the visual pathways (optic neuritis) to evaluate the drug’s effect on remyelination. Results were presented in spring 2015. The primary outcome of RENEW was an assessment of recovery of optic-nerve function measured by the speed at which the nerve conducts visual signals. This was studied by evaluating a test called Full Field Visual Evoked Potential (FF-VEP) in participants treated with anti-LINGO-1, compared with placebo.

Patients who were treated with at least five of the six doses of anti-LINGO-1 showed a 34-percent improvement in optic-nerve conduction latency (delay in the speed of the visual signal) at week 24, compared with placebo. Further recovery in optic-nerve conduction was observed at the last study visit (week 32), with a statistically significant 41-percent improvement. Together, the data demonstrate evidence of treatment effect with continuous improvement observed 12 weeks following the last study dose.

The study showed no effect on secondary endpoints, including change in thickness of the retinal layers (optic nerve neurons and axons) as measured by optical coherence tomography (OCT), or on visual function, measured by a test of vision called low-contrast letter acuity. Anti-LINGO-1 was generally well-tolerated in this study, noting that two patients had hypersensitivity (allergic) reactions at the time of infusion, and one patient had liver function test abnormalities, which resolved after drug discontinuation. Taken together, these results provide an encouraging indication that anti-LINGO-1 appears safe and may facilitate remyelination, though meaningful clinical outcomes will need to be assessed in larger trials.

To that end, a second, larger Phase II trial (SYNERGY)30 is looking at this drug in combination with Avonex. The study will recruit approximately 400 patients with both RRMS and SPMS, and will 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 to prove efficacy. These include measurements of recovery or improvement on physical, visual, cognitive, and other functional assessments of the effects of MS.

Results will provide clinical information about this drug’s efficacy for neuroprotection or repair within the central nervous system (CNS). The results will also address two fundamental questions: 1) Are the effects seen in the optic neuritis study replicable in other areas of the nervous system? And 2) Does this translate to improved function in patients with MS either in the short or long term?

Other experimental treatments under investigation to potentially foster remyelination or myelin repair include agents in early stages of development – and still with experimental names – such as GSK23951231 and rHIgM22.32 Proof-of-principle data are expected for both of these agents in 2016.

Amiloride, Phenytoin, and Sodium Channel Blockade: The accumulation of salt and potassium within the cells of MS lesions may possibly contribute to cellular injury and neurodegeneration (the breakdown of nerves). This hypothesis would suggest that by blocking certain channels in these cells, the buildup of these molecules can be prevented and neurodegeneration can also be prevented. This strategy was tested and data presented in 2013,33 looking at the use of amiloride – a potassium-sparing diuretic approved for the treatment of high blood pressure and congestive heart failure. This medication may have the potential to provide this neuroprotective activity.

The effect of amiloride was studied in 14 people with PPMS using MRI markers of neurodegeneration as outcome measures of neuroprotection. Patients with PPMS underwent MRI scans before and during amiloride treatment, at a standard dose used for high blood pressure, for a period of three years.

Researchers found a significant reduction in the development of brain atrophy, as well as a slowing of the development of disability during the treatment phase. This suggests that amiloride may exert neuroprotective effects in patients with PPMS. Because amiloride does not readily cross the blood-brain barrier to gain access to the CNS, the precise mechanism for these results is not clear. This pilot study was the first effort in people with MS to focus on neuroprotection using amiloride, and supports further investigation of this drug as a potential neuroprotective agent in MS.

A Phase II trial studying this agent in optic neuritis34 was initiated in 2013 and data is expected in 2016. This study is similar in principle to the RENEW study of anti-LINGO-1 as discussed above, as the attempt is to foster protection and repair in the optic nerve in the acute phase after optic neuritis.

It is worth noting that this strategy was successful in a study of the anti-seizure medication phenytoin (brand name Dilantin®), which also works by modulating sodium channels. A Phase II clinical trial assessed whether phenytoin could be neuroprotective in acute optic neuritis35 (AON). The study was comprised of 86 people with AON randomized within two weeks of symptom onset to receive either phenytoin (4 mg per kg daily) or placebo for three months. The primary outcome of this AON study was an evaluation of the structure of the retinal nerve fiber layer (RNFL) and macular volume (MV) at six months. Visual function, optic-nerve imaging, and visual-evoked potentials were also measured.

Of the original 86 participants, 81 were followed to study end. In these patients, the average adjusted affected eye RNFL thickness at six months was higher in the active group versus placebo, resulting in a 30-percent protective-treatment effect. Adjusted MV (macular volume) showed a 34-percent protective-treatment effect. Vision generally recovered well, with no significant difference in visual outcomes between the treatment groups.

This intriguing study may have broad implications, as it found that the administration of a well-known, relatively safe drug seemed to be neuro-protective in the period directly following optic neuritis. Both amiloride and phenytoin may also represent potential combination strategies in conjunction with immune-modulating, disease-modifying therapies.

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 idebenone,36 sponsored by the National Institute of Neurological Disorders and Stroke, recruited participants with PPMS who had little to moderate disability. The trial began in July 2009 and is scheduled for completion in September 2016, with an extension trial continuing through 2018.

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. As a side note to help explain this type of immune-system defense, the “innate” or “natural” immune response is nonspecific. It does not have any type of memory, and reacts in the same way each time it encounters a foreign entity, such as a virus or bacteria. MIS416 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. A further Phase II study37 in SPMS is planned to be completed in late 2016.

Transdermal Administration of Peptides: A small Polish study of 30 individuals38 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 placebo. 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, as measured by the Expanded Disability Status Scale (EDSS), was slightly lower, indicating that disability did not worsen, and may have slightly improved. Additionally, 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 of using a combination of peptides may be pursued in future studies.

IL-17 Modulators: Secukinumab (AIN457) and CJM112. IL-17 is one of several cytokines produced by the immune system. Cytokines are small proteins that may stimulate or inhibit the function of other cells. IL-17 appears to be a major inflammatory component in MS.

Secukinumab is a humanized monoclonal antibody to IL-17. A preliminary study39 administered AIN457 by intravenous infusion to a very small number of patients with psoriasis, rheumatoid arthritis, and uveitis with variable results. A proof-of-concept trial in RRMS40 enrolled 73 patients and showed a reduction in gadolinium-enhancing MRI lesions compared with placebo.41

A larger, Phase II trial was planned to enroll approximately 380 patients with relapsing MS; the design of the study was presented at ECTRIMS in fall 2013, but was cancelled in favor of the clinical development of CJM112, which also targets IL-17 and is administered by subcutaneous injection. The design of the Phase II trial was presented at ECTRIMS in the fall of 2015. To date, no individuals with MS have received this experimental treatment.

SB-683699 (firategrast) is an oral agent thought to reduce the number of active white blood cells entering the brain. It works via a similar mechanism to Tysabri. It had positive results in a Phase II trial42 using gadolinium-enhancing lesions as the primary outcome.

ATL1102 is an oral agent that affects the VLA-4 system, the same molecular mechanism utilized by Tysabri. It does so via a novel mechanism of action, and falls into a class of “antisense oligonucleotides” not previously used in MS. The results of a Phase II trial were published in 201443, noting that ATL1102 decreased the emergence of new active brain lesions as compared with placebo, after only two months of treatment in approximately 70 RRMS patients. As of 2015, the development path for this agent is still being considered.

Pixantrone (PIX) is under investigation as an alternative for the effective but cardio-toxic drug Novantrone® (mitoxantrone or MIX) in the treatment of aggressive RRMS or SPMS. In a Phase I/II study of 18 patients with aggressive disease, results presented in 201444 showed that pixantrone was as effective as Novantrone, but with less cardiotoxicity. Although via a different mechanism of action than rituximab and ocrelizumab, pixantrone was shown in this study to reduce B cells by 95 percent. According to the study abstract,45 pixantrone is structurally similar to Novantrone and both drugs have similar immuno-suppressive properties in animal studies. However, the authors state that pixantrone is less toxic to the heart.

SR-CRH-01 is a stabilized, neuropeptide, also known as Aimspro®. In a Phase II double-blind, placebo-controlled study of 20 people with SPMS presented in 2014,46 SR-CRH-01 was well-tolerated when given by subcutaneous injection twice weekly for four weeks, resulting in significant improvements in several secondary endpoints. These endpoints included the MS Functional Composite (MSFC), the Timed 25-Foot Walk (T25-FW), and the mean 9-Hole Peg Test (9-HPT). Larger, longer-term studies are warranted given these promising results. However, no new trials are presently being conducted.

New Directions in MS Research

New Therapeutic Approaches

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.

More than ever, the field of MS research relies upon the willing participation of patients in clinical trials. We now recognize how ethnically, racially, genetically and culturally diverse the MS community is, but diversity in our clinical trial populations is lacking. In 2015, data from six randomized, placebo-controlled trials were used to examine the baseline characteristics and clinical outcomes in white, black, Asian, and Hispanic populations. The results were challenging to interpret due to the incredibly low number of non-white participants in clinical trials, which in turn makes our clinical trial results hard to interpret in the real world. The field of MS research needs a diverse population recruited into clinical trials if we are to truly know that our medications are globally effective in MS.

Despite the setback of unsuccessful trials in progressive MS, ongoing clinical trials in both 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, with more on the way. 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.

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