ECTRIMS Update 2011
Highlights from the ECTRIMS/ACTRIMS Joint Meeting – Amsterdam, October 19-22, 2011
October 19-22, 2011
This year’s joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS) was extremely well attended. More than 7,000 professionals attended the meeting, which featured more than 1,000 presentations – all in a whirlwind three-and-a-half days.
The following highlights review only a few of the many topics discussed at the meeting, but they reflect research of ongoing interest to the entire MS community.
Phase III Results For New Drugs and Related Studies
The most notable event was the release of data from Phase III trials for five drugs, all of which were tested in relapsing-remitting MS (RRMS). These drugs have been discussed previously in MSAA’s “Research Update,” appearing annually in The Motivator. The most recent update may be found in the Summer/Fall 2011 issue.
Alemtuzumab (Lemtrada®, formerly Campath)
This drug is administered in one course yearly by intravenous infusion over three-to-five consecutive days. It is a humanized monoclonal antibody that targets a protein present on the surface of mature lymphocytes and is approved for the treatment of B-cell leukemia.
Results from the Phase III CARE-MS I study compared Lemtrada to Rebif® over a two-year period. The study showed that trial participants treated with Lemtrada had an Annual Relapse Rate (ARR) that was 55-percent lower than for individuals taking Rebif, as well as an increased reduction in T2-hyperintense lesion volume (as indicated by the “hyper” prefix, this refers to lesions with increased intensity). No difference was observed between the two drugs in the ability to reduce the progression of disability.
The Phase III CARE-MS II study tested Lemtrada against Rebif in patients who relapsed while on a therapy for MS. The results were released a few weeks after the meeting. The press release indicates that patients taking Lemtrada during the two-year study period experienced a 49-percent reduction in relapse rate compared to those taking Rebif. The Lemtrada group also had a 42-percent reduction in the risk of sustained accumulation (worsening) of disability as measured by the EDSS. (“EDSS” refers to the Kurtzke Expanded Disability Status Scale, which measures disability in numbers from 1 to 10.)
BG-12 (dimethyl fumarate)
BG-12 is an oral medication taken daily. It may have a distinct dual mechanism of action. First, it is an immunomodulator with anti-inflammatory properties. This induces anti-inflammatory cytokines (small proteins that may stimulate or inhibit the function of other cells) and appears to suppress damaging macrophage cell activity. Second, BG-12 may also have neuroprotective effects.
The DEFINE Phase III study tested 240 mg of drug given either twice or three times daily, compared to an inactive placebo. The treated group had an approximate 50-percent reduction in the proportion of patients who had relapsed at the end of two years compared to those taking a placebo. The ARR was reduced by 48 to 53 percent; the mean number of T2-hyperintense lesions was reduced by 73 to 85 percent; and the mean number of new T1-hypointense lesions (as indicated by the “hypo” prefix, this refers to lesions with a lower intensity) was reduced by 63 to 72 percent.
Laquinimod is an oral medication taken once daily. It has been granted Fast Track status by the United States Food and Drug Administration (FDA). Although its exact mechanism of action is unknown, it is an immunomodulator, apparently through its effects on cytokines and interleukins. It enhances T-regulatory cell activity, which reduces Th1-inflammatory T-cell activity. It also appears to reduce white blood cell penetration of the central nervous system (CNS). In addition to its immunomodulatory actions, laquinimod may have neuroprotective effects in people with MS.
The BRAVO Phase III trial did not meet its primary endpoint of reducing ARR relative to placebo. However, after adjustment for baseline differences (for clinical factors associated with relapse rate that were imbalanced between the three treatment groups), there was a 33.5-percent decrease in three-month disability progression and 40.6-percent decrease at six months. These reductions are compared to Avonex®, which showed a 29-percent decrease compared to the placebo group. Approximately 12 percent of the placebo group showed a confirmed six-month disability progression, compared with approximately 7 percent on laquinimod and 8 percent on Avonex. The group receiving laquinimod had significantly lower brain atrophy (a loss of brain volume due to cell death and demyelination) during this period; it was 1.25 percent with Avonex, 1.14 percent with placebo, and 0.83 percent with laquinimod.
Zenapax is administered via intravenous infusion every four weeks and has also been studied when given in subcutaneous injections. It is a genetically engineered monoclonal antibody that binds to CD25, a receptor on T cells that is thought to become activated in MS. Zenapax is believed to selectively target these activated T cells without causing general T-cell depletion. It is approved by the FDA for use in rheumatoid arthritis and other autoimmune diseases.
The SELECT trial results showed a decrease in ARR of 54 percent and a decrease in disability progression of 57 percent, as compared to placebo. The proportion of patients who were relapse-free at one year was 63 percent for placebo and 80 percent with Zenapax . The confirmed three-month disability progression was reduced to 6 to 8 percent (in the two groups receiving one of two dose levels of Zenapax ) from 14 percent for placebo. The number of new lesions was also decreased, from 4.8 with placebo to 1.0 to 1.5 in the treated groups. A significant improvement in secondary outcomes was also seen in the treated groups, including physical function, disability progression, and T2-hyperintense lesion burden as shown on magnetic resonance imaging (MRI).
Teriflunomide is an oral medication taken daily. It is an immunomodulator that affects the production of T and B cells. It inhibits rapidly dividing cells, including activated T cells, which are thought to drive the disease process in MS. It may inhibit nerve degeneration by reducing the production of free radicals, possibly decreasing the risk of infections and other complications linked to chemotherapy-like drugs.
Open-label extension studies of this drug, now under FDA review in the United States, showed a 31-percent decrease in the ARR versus placebo, and a reduction in disability progression of 29.8 percent versus placebo. The EDSS remained stable for the group given the higher dose of 14 mg/day, and rose only moderately among those on 7 mg-dose per day.
Ocrelizumab is administered via intravenous infusion. It is a monoclonal antibody that binds to a receptor on the surface of B cells. These cells are then destroyed and their levels in the circulation are decreased. Similar to the drug Rituxan (another anti-CD20 monoclonal antibody), ocrelizumab has the potential advantage of being a more humanized antibody than Rituxan.
While Phase III studies have largely been the topic of this article so far, the results of an important Phase II study reported at the meeting indicated that ocrelizumab maintained a significant reduction in disease activity in patients with RRMS for almost two years.
A Phase III clinical program (ORCHESTRA) is underway, which will test the drug in people with RRMS (Opera I and II) and in people with PPMS (Oratorio). According to www.clinicaltrials.gov, the PPMS portion of this program has two treatment arms (ocrelizumab and placebo) and will evaluate the efficacy and safety of ocrelizumab in patients with primary progressive multiple sclerosis . The blinded treatment period will be more than two years (at least 120 weeks), followed by an open-label treatment for patients in both groups who (in the opinion of the investigators) could benefit from further or newly initiated ocrelizumab treatment. This study is expected to take up to five and half years to complete.
Tysabri is administered via intravenous infusion every four weeks. It is approved for all individuals with relapsing types of MS. This drug is generally recommended for patients who have not responded adequately to, or who cannot tolerate, another treatment for MS.
This laboratory-produced monoclonal antibody acts against a molecule involved in the activation and function of lymphocytes (immune-system cells produced to fight infection and disease) and their migration into the CNS. Recent data suggest that it may also enhance remyelination and stabilize damage to the myelin sheath (the protective covering of the nerves). Preliminary results suggest that the drug may actually produce an improvement in function.
Discontinuing Tysabri to reduce the risk of Progressive Multifocal Leukoencephalopathy (PML), an often-fatal viral infection of the brain, was associated with a rapid return of MS disease activity. A report from the Cleveland Clinic indicated that more than half of patients in the RESTORE trial who switched to methylprednisolone (a steroid) or Copaxone® for six months, relapsed or developed new gadolinium-enhancing lesions. This was also true for four of 14 patients who switched to Avonex.
Note about Primary-Progressive Multiple Sclerosis (PPMS)
Unfortunately, no research studies on PPMS were presented at the ECTRIMS/ACTRIMS joint meeting. As the author of this article, I wish I had more to report. The good news is that several clinical trials are now in progress. Anyone looking for more information on the topic of PPMS research and current studies may refer to a recent online article from MSAA.
The Value of Early Treatment
It is becoming clear from a number of lines of evidence that “benign” MS may not be benign at all, and that early treatment leads to better long-term outcomes. The old approach of “wait and see how the disease progresses, because it might be mild,” has given way to the “treat early” concept. Improved technology now shows that MS damage to a number of brain areas, as well as demonstrable cognitive changes, can be seen even in people with a first attack – referred to as clinically isolated syndrome (CIS). Long-term studies show improvement in longevity with early treatment. Individuals with more T2-hyperintense lesions on MRI at the time of CIS diagnosis have greater disability at 14 years. The same appears to be true for early cognition problems.
Grey Matter Damage in MS Linked to MS Progression
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. 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.
As noted by J.J.G. Guerts of the VU University in Amsterdam, as well as other clinicans and researchers, the “something else” (that must be going on when MS progresses) appears to be grey-matter pathology. This is missed on standard imaging, which – in his words – only shows the “tip of the iceberg.” 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.
Grey-matter atrophy drives whole-brain atrophy, and is related both to clinical outcome and disease progression, including cognitive changes. Cognitive defects appear to be at least partially related to damage in the hippocampus, an area of the brain that plays important roles in consolidating information from short-term to long-term memory, as well as navigating in space. Individuals with greater hippocampal grey-matter atrophy are more impaired in learning new information, although there seems to be no effect on processing information once it is learned.
Richard Rudick, MD, of the Cleveland Clinic noted that the clinical consequences of grey-matter damage begin early in the course of the disease and increase with advancing MS. It predicts the conversion of CIS to RRMS, and correlates well with both current and future MS-related disability. The effect of drugs on grey-matter pathology is not yet known, but it would be an attractive outcome measure in future drug studies since it correlates with both physical and cognitive damage.
Longevity and MS
Although it has long been said that MS is not a fatal disease, healthcare professionals have known for many years that people with advanced MS sometimes die as the result of complications of the disease, most often infections such as aspiration pneumonia and sepsis (a condition in which a bacterial infection spreads throughout the body by way of the bloodstream). But this data has never been quantified.
Based on population registries and other sources, it is now apparent that in the past, MS has carried an eight-to-12 year shortening of life on average. However, life expectancy for people with MS has been steadily improving decade-by-decade since the 1950’s, most likely a result of improved general health and the availability of better healthcare. Studies from the Betaseron 21-year data indicate that people in the earliest study of the drug who were in the active-treatment group for five years, showed significantly improved longevity as compared to those who received placebo at that time – this is irrespective of whether they did or did not go on active treatment at a later date. This evidence is still not complete, but it does point to the benefits of early treatment, as does the information on cognitive issues.
Cognition and MS
While the EDSS is an excellent scale to measure mobility and other physical symptoms in MS, the fact that it is not adequate for evaluating cognitive issues has been apparent for a long time. The international initiative called BICAMS (Brief International Cognitive Assessment for MS) is developing a practical cognitive assessment tool that is intended to be as useful for assessing cognitive problems in MS as the EDSS is for physical ones.
Drs. Iris Penner at the University of Basel in Switzerland and John DeLuca at the New Jersey Medical School reviewed current studies in cognition and cognitive rehabilitation. The component of cognition that is most affected in early MS is “working memory.” The primary cognitive problem for people with MS is learning new information. This appears to be the result of decreased speed of processing information. Fortunately, the retrieval process is relatively normal once material has been learned.
Cognitive changes can even be detected in patients with no symptoms of MS but who have an abnormal MRI. This is called radiologically isolated syndrome (RIS), which is an even earlier stage than CIS or a first attack. Earlier treatment is, for example, linked to a better PASAT cognition score at five years. The PASAT is the Paced Auditory Serial Addition Test, which is a measure of cognitive function.
In the most recent issue of The Motivator, biomarkers are discussed at some length. This topic was also a major focus of a number of presentations at ECTRIMS/ACTRIMS, as well as the prestigious Charcot Award Lecture by Dr. Lawrence Steinman of Stanford University. Progress continues to be made, both in terms of determinants of disease activity and therapeutic response to disease-management therapies.
An increasing number of studies have linked specific genes and the proteins, whose manufacture they control, to MS. They are bringing us closer to being able to use biomarkers to predict who will have a more severe course of disease and who will respond to therapy.
Chronic Cerebrospinal Venous Insufficiency (CCSVI)
A number of studies reported at ECTRIMS provide little support for the concept that CCSVI is related to the development of MS. For example, one of the largest studies to date, which included 160 patients and 160 healthy controls, was conducted at the University Hospital in Padova, Italy. It found no evidence that CCSVI is a possible cause of MS. Other studies, by groups in Israel, Hungary, Australia, Germany, and the United States, also failed to show a correlation. However, the data remains inconclusive; a study from the Cleveland Clinic showed abnormalities in the veins that flow out of the CNS in six of seven people who died with MS as compared to one in seven individuals without MS. The relevance of these data is as yet unknown.
Written by Diana M. Schneider, PhD
Reviewed by Jack Burks, MD, MSAA Chief Medical Officer
Edited by Susan Wells Courtney, MSAA Senior Writer and Creative Director