MS Research Update 2015
Published in April 2015, this update is a comprehensive overview of research findings on the FDA-approved disease-modifying therapies, as well as many experimental treatments
Written and compiled by Stephen Krieger, MD
Includes material by Margaret M. McCormick, RN, BSN, MSCN and Diana Schneider, PhD
Reviewed by Jack Burks, MD | Edited by Susan Wells Courtney
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). Many studies are limited to relapsing forms of MS, so for easier recognition, trials with progressive forms of MS have been highlighted in bold.
While this 2015 edition of the MS Research Update reflects the incredible diversity and scope of research progress in MS, space does not allow for all of this research to be covered. Therefore, this is not a complete list of study results.
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 as well as international conferences. These include the 2014 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).
More than 20 years have passed since the United States Food and Drug Administration (FDA) approved Betaseron, the first disease-modifying therapy for MS, and the beginning of the MS-treatment era. This medication, and others 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.
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 year 2014 saw the approval of a new formulation of Copaxone, dosed three times per week versus daily. The year also saw a new type of interferon called Plegridy, which is dosed once every two weeks. A new agent given by a series of infusions once yearly, Lemtrada, was approved by the FDA at the end of 2014, making it the third newly approved treatment for MS in less than one year.
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 paper will be updated as new treatments become available.
This professional paper, titled “The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence,” was published in August 2014 and has been distributed to thousands of MS medical professionals. In November 2014, a summary was published. This is written in a more reader-friendly style to better serve the broader MS community. It shares the same title, with the addition of the word “SUMMARY” at the end. Both of these papers are available on MSAA’s website by going to mymsaa.org, selecting “News from MSAA,” and then scrolling down to those two papers (listed in order of publication date).
Please note that in this MS Research Update, 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.
For information on trial phases, please refer to the inside-back cover of this publication. For any other questions about MS, or to learn more about MSAA’s vital services and support, please visit mymsaa.org or call (800) 532-7667.
Administered by Self-Injection
- Avonex® (interferon beta-1a)
- Betaseron® (interferon beta-1b)
- Copaxone® (glatiramer acetate)
- Extavia® (interferon beta-1b)
- Plegridy™ (PEGylated interferon beta-1a)
- Rebif® (interferon beta-1a)
Administered by Intravenous (IV) Infusion
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 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.
- Daclizumab (Zinbryta™)
- Rituxan® (rituximab)
- Ofatumumab (also known as Arzerra®)
Other Therapeutic Strategies
- New S1P Receptor Modulators
- Siponimod (BAF312)
- Masitinib (also known as Kinavet® and Masivet®)
- Tcelna™ (formerly Tovaxin®)
- Tetracycline Antibiotics
- Vitamin D3
- Chronic Cerebrospinal Venous Insufficiency (CCSVI)
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 invest-igation. 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 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 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 trials77, 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.
The first Phase II trial of anti-LINGO, called RENEW, launched in 2013.78 The study recruited patients with newly-diagnosed MS involving the visual pathways (optic neuritis) to evaluate the drug’s effect on remyelination.
Anti-LINGO-1 demonstrated an improve-ment in the study’s primary endpoint, which was the extent of recovery of the optic nerve after optic neuritis as compared to placebo. This was measured by full field visual evoked potential (FF-VEP), an electrical test of the speed that the optic nerve sends visual signals to the brain.
The study showed no effect on secondary endpoints, including change in thickness of the retinal layers (optic nerve neurons and axons). Anti-LINGO-1 was generally well tolerated in this study, noting that two patients had hypersensitivity 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.
To that end, a second, larger Phase II trial (SYNERGY)79 is looking at this drug in combination with Avonex. The study will recruit approximately 400 individuals with either RRMS or SPMS. It 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.
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, 2013.80
Other agents under investigation to potentially foster remyelination or myelin repair include agents in early stages of development – and still with experimental names – such as GSK23951281 and rHIgM22.82 Proof of principle data are expected for both of these agents in 2015.
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, and these include one that is evaluating erythropoietin as an adjunct treatment for optic neuritis.83
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.
A double-blind, placebo-controlled Phase I/II clinical trial of idebenone,84 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. A further Phase II study85 in secondary-progressive MS is enrolling, with completion planned for late 2016.
Transdermal Administration of Peptides: A small Polish study of 30 individuals86 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. Additionally, progression as measured by the Expanded Disability Status Scale (EDSS) was slightly lower, indicating that disability did not worsen, and may have slightly improved, plus 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.
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:
Secukinumab (AIN457) is a humanized monoclonal antibody to IL-17. A preliminary study87 administered AIN457 to a very small number of patients with psoriasis, rheumatoid arthritis, and uveitis with variable results. A proof-of-concept trial in RRMS88 enrolled 73 patients and showed a reduction in gadolinium-enhancing MRI lesions compared with placebo.89 A larger, Phase II trial has been planned to enroll approximately 380 patients with relapsing MS; the design of the study 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 2012.90
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 placebo-controlled Phase II trial91 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 falls into a class of “antisense oligonucleotides” not previously used in MS. The results of a Phase II trial were published in 2014,92 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.
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 secondary-progressive MS (SPMS). In a Phase I/II study of 18 patients with aggressive disease presented in 2014,93 pixantrone was as effective as Novantrone with less cardiotoxicity. According to the study abstract, pixantrone is structurally similar to Novantrone and both drugs have similar immunosuppressive properties in animal studies, but may be 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 2014,94 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, and the mean 9-Hole Peg Test (9-HPT). Larger, longer-term studies are warranted given these promising results.
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. And ongoing clinical trials in PPMS and SPMS, as well as invest-igations 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, including FDA-approval of new agents since the previous edition of this MS Research Update was published. 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.