Highlights from The Consortium of Multiple Sclerosis Centers Annual Meeting, Held in San Diego (May 31 – June 4, 2012)
Editor’s note: For easier reading, certain definitions have been included within the text and are often repeated throughout the article. Additionally, for easier reading, a brand name of an approved drug is used versus the generic name wherever possible.
The Consortium of Multiple Sclerosis Centers (CMSC) annual meeting provides a unique opportunity for MS professionals to come together in an interdisciplinary setting to discuss all aspects of MS care. Attendees include physicians, nurses, physical and occupational therapists, psychologists, social workers, and other MS professionals. Topics are wide-ranging, from the latest advances in research and symptom management, to practical workshops designed to improve hands-on care.
To follow are a few selected topics that may be of particular interest to the MS community.
New Agents under Review by the FDA
Within recent months, the development of new drug therapies for MS has been progressing rapidly. This is largely because clinical trials of potential treatments that have been ongoing for years are now either complete or nearing completion. At the time of this writing, three drugs are under review by the United States Food and Drug Administration (FDA). To follow are details about these three drugs that were recently submitted for FDA approval.
Teriflunomide is an oral agent taken once daily in pill form. The brand name Aubagio® has been proposed. Results released during the CMSC meeting from the Phase III TOWER trial of oral teriflunomide (in 1,169 patients with relapsing-remitting MS [RRMS]) show a significant reduction in annual relapse rates as well as a significant reduction in sustained accumulation of disability with the 14-mg dose as compared to placebo. Results with a lower dose of 7 mg reduced relapse rate, but did not affect the accumulation of disability. Two additional Phase III trials are still in progress. A decision by the FDA on the approval of teriflunomide is expected this fall.
Dimethyl Fumarate (DMF), formerly known as BG-12, is also an oral agent. In clinical studies, it was given either twice or three times daily. Results from clinical trials were presented at the American Academy of Neurology (AAN) annual meeting in April. In general, DMF reduced the amount of brain atrophy (shrinkage) over the course of two years, significantly reduced MS-related lesion activity, and significantly reduced annual relapse rates compared to placebo.
Alemtuzumab (Lemtrada®), formerly known as Campath, is given intravenously for five days, and then a second time one year later for three days. Data were collected for each patient during a two-year period from the time of the first infusion. As with DMF, results from clinical trials were presented at the American Academy of Neurology (AAN) annual meeting in April. In general, alemtuzumab significantly reduced MS-related lesion activity (and other positive MRI data) and significantly reduced annual relapse rates, compared to Rebif® (interferon beta-1a).
For more information on study results with DMF and alemtuzumab, please refer to MSAA’s online article, Highlights from the American Academy of Neurology’s Annual Meeting, Held in New Orleans (April 21-28, 2012).
Copaxone Results for Lower Frequency Dosing Announced
Results were announced in mid-June for the Glatiramer Acetate Low-Frequency Administration (GALA) trial that studied the effect of a more concentrated and long-acting version of the drug. A higher dosage of 40 mg given by subcutaneous (under the skin) injection three times per week was compared to the currently approved dose of 20 mg given daily (also via subcutaneous injection). Approximately 1,400 individuals were involved in the trial. The new formulation reduced the annualized relapse rate (ARR) by 34 percent as compared to placebo. The makers of Copaxone® (Glatiramer Acetate) indicated that the study also met other secondary goals. More detailed data are to be presented in the near future.
Progressive Multiple Sclerosis and Neurodegeneration
In a presentation, the difficulties that have hindered a better understanding of the mechanisms that underlay progression in MS were summarized. They include an incomplete understanding of the underlying processes, clinical problems with trial design, the lack of good short-term outcome measures and biomarkers (in contrast to the excellent MRI measures that can be used for relapsing-remitting disease), and the difficulty of obtaining sufficient numbers of patients for trials.
Atrophy – the decrease in the volume of brain tissue often associated with MS – has taken center stage in MS clinical trials, especially those focusing on progression and degeneration. Eventually, measures of atrophy may replace the current focus on gadolinium (Gd)-enhancing (active) lesions that have been a key measure when studying relapsing disease. One approach is to look for substances or biological processes that might limit neurodegeneration (damage to nerves) in early MS, such as those that might enhance structural and functional repair.
One clear trend in studying progressive MS has been an increased emphasis on grey matter in the brain – in contrast to the white matter that has been the focus of research in RRMS. For example, more information about the accumulation of grey matter injury in progressive MS is expected in the near future.
In MSAA’s online article, Highlights from the ECTRIMS/ACTRIMS Joint Meeting – Amsterdam, October 19-22, 2011, the differences between grey and white matter are described as follows:
“Because white matter in the brain shows up well with standard MRI scans, it has been the focus of MS studies for many years. White matter mainly consists of tracts of myelinated nerves. [myelin is the protective covering to the nerves]. However, white matter has never been possible to demonstrate a strict correlation between damage to white matter and MS progression. Researchers have speculated that ‘something else’ must be going on when MS progresses.
“But white matter is only one of the two components of the central nervous system. The other is grey matter, which accounts for a large amount of total brain tissue. Grey matter consists of neuronal cell bodies as well as both myelinated and unmyelinated nerves, along with other types of cells.
“…A new type of MRI, called ‘DIR’ (double inversion resonance imaging), is capable of visualizing grey matter. It is becoming apparent that grey-matter pathology correlates much better than white with cognitive issues as well as physical progression. This has been verified on postmortem examination.”
Please refer to MSAA’s online article, Highlights from the ECTRIMS/ACTRIMS Joint Meeting – Amsterdam, October 19-22, 2011, for more information.
A Potential Treatment for Progressive Multiple Sclerosis?
Although not presented at the CMSC, MSAA strives to provide information on progressive MS, since so little has been available for treating this type of MS. In mid-June, results from a Phase II study of 30 patients with masitinib were released. These indicated what is termed “proof of concept,” showing that this agent may have potential in treating both PPMS and relapse-free SPMS.
Masitinib is termed a protein kinase inhibitor. It selectively inhibits molecules (kinases) that play a major role in the activation of mast cells. Mast cells are involved in the immune response, in the recruitment of lymphocytes to the brain (lymphocytes are immune-system cells produced to fight infection and disease), and also in inflammatory processes associated with MS. A Phase III study is planned.
The study investigated the hypothesis that masitinib’s action of targeting and inhibiting mast cells may delay the onset of symptoms associated with progressive forms of MS. The results showed that for the primary endpoint of Multiple Sclerosis Functional Composite score (MSFC), which measures upper and lower limb function as well as cognition, 32 percent of patients treated with masitinib showed a response to treatment versus none of those receiving a placebo. Responses were seen in the third month and were sustained over the 18-month duration of the study.
More About Biomarkers and Surrogates
Biomarkers were discussed in MSAA’s online article, Highlights from the ECTRIMS/ACTRIMS Joint Meeting – Amsterdam, October 19-22, 2011, as well as in the cover story, Multiple Sclerosis Research Update from the Summer/Fall 2011 issue of MSAA’s magazine, The Motivator. Biomarkers were also a major topic of discussion at this year’s CMSC meeting.
A biomarker is defined as anything that can be found in blood, other body fluids, or tissues that is a sign of a particular disease state. For example, elevated blood pressure is a biomarker of risk for stroke. Biomarkers can be used to see how well the body responds to a given treatment. A biomarker may also become a potential surrogate in clinical trials. A surrogate in this instance is a laboratory measurement or physical sign that acts as a substitute for a clinically meaningful endpoint, providing a direct measure of outcome.
MRI is the most common surrogate used in clinical trials, and it is also used as a marker of whether a patient’s disease is progressing or not. Recent modifications to the McDonald Criteria (a set of guidelines used to confirm a diagnosis of MS) help neurologists to make an earlier diagnosis of MS. These changes are primarily related to early MRI indicators of the presence of disease. Earlier diagnosis can result in earlier treatment, often at the time of a first attack, which has been shown to be associated with better outcomes. Specific features of the MRI are also predictive of how well an individual’s outcome may be over time.
Biomarkers are now used to guide therapy in MS, as they are increasingly correlated with responses to disease-modifying agents, including the interferons (Avonex®, Betaseron®, Extavia®, and Rebif®), Copaxone®, and Tysabri®. Many potential biomarkers are being explored. These are expected to lead to the development of patient “screens” that will be a profile with components related to immunology, clinical phenomena, pathology, and imaging. These biomarkers may also help to predict who will or will not respond to a given therapy.
Ongoing research is attempting to identify biomarkers that will help select the best disease-managing therapy for each individual. Researchers are seeking biomarkers that may predict results before starting treatment, and markers to indicate whether a therapy is effective
Learning and memory issues interfere with everyday life in MS. They are believed to affect at least half of all people with MS, and have major effects on family life, employment, and other areas of everyday living.
The cognitive issues in MS arise from problems with:
- thinking in general
- understanding language and being able to express one’s thoughts
- concentration, the ability to shift attention, and multitasking
- learning and remembering
- planning and performing complex tasks
As noted in earlier reports, cognition has now been shown to be associated with grey matter damage. This explains our previous inability to show a correlation between MS-associated cognitive decline and brain lesion activity as seen on MRI. This is because with MS, the MRI has primarily measured the effects on white matter, which consists of myelinated neurons, i.e., nerves with the protective myelin covering.
Atrophy (the decrease in brain-tissue volume) is associated with cognitive impairment, especially when it occurs in the frontal portions of the brain that are most involved with intellectual function. In addition, damage to specific areas in the brain – the thalamus and hippocampus – can now be correlated with cognitive symptoms in MS. It is hoped that this type of data may lead to a better ability to predict which individuals with MS are at risk for developing cognitive issues so that treatment can be initiated earlier in the process.
Individuals with cognitive issues may be helped substantially by cognitive rehabilitation. New techniques are aimed at improving cognition. While this type of rehabilitation cannot restore lost function, it can help to maximize existing capacity. Its aim is to restore as much independence as possible.
The lack of an effective tool to measure cognitive changes in MS – similar to the way the EDSS is used to measure physical changes – has hampered the ability to identify and measure the extent of cognitive impairment in an individual. The international BICAMS project – Brief International Cognitive Assessment for MS – has been in development for several years. It is intended to provide a brief cognitive assessment tool that can be used by health professionals who are not cognitive specialists, and also serve as a standard measure internationally. The group involved in this study has now recommended a brief cognitive assessment program that involves three basic tests, with the goal of providing a reliable and sensitive assessment of cognition. Hopefully, the availability of this evaluation tool will lead to earlier diagnoses of cognitive impairment, and in turn, to earlier opportunities for developing compensating strategies.
Written by Diana M. Schneider, PhD
Reviewed by Jack Burks, MD
Edited by Susan Wells Courtney