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More than 10,000 researchers and practicing neurologists from around the world gathered at the 60th Annual Meeting of the American Academy of Neurology in Chicago from April 12-19. A record 338 presentations were related to multiple sclerosis. National MS Society grantees were among those presenting novel findings on many different aspects of MS research. (For free access to the abstracts of presentations given at this year’s meeting, go to:www.abstracts2view.com/aan2008chicago.) Here are a few highlights:
Professor Stephen L. Hauser, MD, received the National MS Society/American Academy of Neurology’s 2008 John Dystel Prize for Multiple Sclerosis Research, for his pioneering studies on genetic susceptibility to MS, and for his role in translating findings on the role of immune B cells in MS into clinical trials.
Dr. Hauser (University of California at San Francisco) spoke strongly about the roadblocks that exist in MS research, in particular, to translating basic findings to new therapies. “The greatest threat to our progress in understanding MS is the fact that the pipeline of outstanding young clinician scientists is falling.” This is a growing area of concern and may be due in part to fewer opportunities for research funding from NIH and higher financial pressures from increasing costs of college and medical school.
He also spoke of the great potential for genetics research. “By 2013 we will know all common variants [genetic variations] that influence MS,” he said. “We will also know why some populations are resistant to MS.” This and other progress in understanding MS genes should help us identify the cause of this disease and pinpoint new therapeutic targets.
Dr. Hauser spoke about the meaning of this award, “This Prize reminds us of the ultimate goal of our research efforts: to help people with MS.”Read moreabout the Prize and Dr. Hauser’s research contributions.
Many presentations focused on new data analyzed from ongoing or completed clinical trials in multiple sclerosis. Following are a few examples of the exciting work being done by investigators and pharmaceutical and biotechnology companies around the world.
• A previously reported six-month, phase 2 controlled study of oral
(FTY720, Novartis Pharma AG) showed possible benefits in relapse rate and MRI-detected disease activity in relapsing MS, and the drug is now being tested in a larger,phase 3 trial. Fingolimod binds to a docking site (sphingosine-1-phosphate receptor, or S1P receptor) on immune cells, including T cells and B cells, that have been implicated in causing nervous system damage in MS. Dr. Giancarlo Comi (Vita-Salute San Raffaele University, Milan) and colleagues reported on a 36-month extension study of the phase 2 trial, in which all participants were put on active therapy. After three years, 173 participants were still in the study. Results showed that 73% of patients who began the study on FTY720 5 mg remained free from relapses after three years, and 68% of those who began the study on FTY720 1.25 mg remained relapse-free. Results also showed an average annualized relapse rate of 0.20 (meaning one relapse in five years) and 89% were free of active brain lesions on MRI (vs. 84% at two years). (Abstract #S12.005, funded by Novartis Pharma AG) According to a press release, the company expects to file for regulatory approval before the end of 2009.
• Dr. Hideki Garren (Bayhill Therapeutics) and colleagues reported additional data from a phase II study of
(one of two doses (.5 mg or 1.5 mg) vs. inactive placebo) in 289 people with relapsing-remitting MS. BHT-3009 is a vaccine containing genetic material that instructs cells to produce myelin basic protein (MBP), a component of myelin, an immune target in MS. It is given by periodic injections into the muscle. While the study did not show a statistically significant difference in active MRI lesions between those on therapy and those on placebo, Dr. Garren’s presentation focused on findings from 80 patients from whom cerebral spinal fluid (CSF) was collected before beginning therapy to profile those patients who responded to the drug based on initial CSF levels of immunoglobulin (IgG). In patients whose IgG levels were greater than or equal to 2.5 mg/dl at baseline, the primary goal of the study was achieved, that is, active lesions observed on MRI scans were reduced from weeks 28 to 48 by 44% versus placebo. Annualized relapse rates for this group were reduced by 36%. Dr. Garren stated that a new trial is in planning stages. (Abstract #S22.003, funded by Bayhill Therapeutics, Inc.)
• Dr. Anjali Shah (University of Texas Southwestern Medical Center, Dallas) and colleagues reported on a study of
injections in 19 people with MS and spastic foot drop. Botulinum toxins are powerful neurotoxins (poisons) that block the release of acetylcholine at the junction of nerves and muscles, a chemical that, among other things, signals muscles to contract. These injections have been shown in clinical trials to relieve spasticity in individual muscles for up to three months, without any significant side effects. In the current study, botulinum toxin type A (150 units diluted in 1 cc of saline) was injected into leg muscles, and patients underwent 6-8 weeks of physical therapy. A significant improvement in spasticity and emotional quality of life occurred, and MS disease activity remained stable. (Abstract #P03.070) Studies of Botox® (botulinum toxin type A, Allergan, Inc.) for neurogenic incontinence are recruiting patients nationwide, and are listed in ourclinical trials database.
• Dr. Michael Kaufman (Carolinas Medical Center, Charlotte) and colleagues reported final results of the phase II “CHOICE” study of
(PDL Biopharma and Biogen Idec) in 230 people with relapsing forms of MS who were taking interferon beta. Daclizumab is a laboratory-created monoclonal antibody that blocks the activity of interleukin-2 receptor-alpha, a key immune activator in MS. In this study, while continuing on their interferon treatment, 78 people received 1 mg daclizumab injection under the skin every 4 weeks, 75 received 2 mg every 2 weeks, and 77 received placebo, for 24 weeks and were observed for 48 weeks afterward. After 24 weeks, compared to interferon and placebo, there was a 25% reduction in the number of new or enlarged areas of active damage on MRI (the primary endpoint of the study) in the 1mg daclizumab group and a 72% reduction in the 2 mg group. Preliminary safety showed a similar overall infection rate across all treatment groups. (Abstract #PL01.003, Supported by: PDL and Biogen Idec)
• Two groups reported on the use of
(LDN). Naltrexone is an opioid antagonist that has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of addictions to opioids and alcohol. At significantly lower doses, it has been prescribed as a treatment for a variety of diseases. Dr. Gianvito Martino (San Raffaele Hospital, Milan, Italy) and colleagues administered 5 mg of LDN to 40 people with primary-progressive MS for 6 months, evaluating its safety and effects on spasticity, pain and fatigue. Five patients dropped out. Significant improvements were shown in fatigue and depression. Transient increases in liver enzymes, urinary tract infections, mild agitation and sleep disturbance were the most common adverse events. (Abstract #P01.149, funded by the Italian Federation of Multiple Sclerosis)
Dr. Bruce Cree (University of California, San Francisco) and colleagues reported that eight weeks of treatment with LDN significantly improved quality of life (specifically, mental health, pain, and self-reported cognitive function) in 60 people with MS as measured by the MS Quality of Life Inventory. No impact was observed on physical quality of life (such as fatigue, bowel and bladder control, sexual satisfaction, and visual function). Vivid dreaming was reported during the first week of treatment by some patients, but no other adverse effects were reported. (Abstract #P02.151) Patient advocates with MS have funded Dr. Cree to conduct a larger, controlled study that will involve 80 people with MS.
• Dr. Alasdair J. Coles (Adenbrooke’s Hospital, University of Cambridge, UK) reported 24-month results from a phase 2 clinical trial comparing high and low doses of the immune-suppressing monoclonal antibody
(Genzyme Corporation) with Rebif® (interferon beta-1a, EMD Serono, Inc. and Pfizer, Inc.) in people with relapsing-remitting MS who had never taken any other disease-modifying therapies. Pooled data on those taking either dose of Campath indicate a 73% reduction in the risk of MS relapse compared with those on Rebif and a 71% reduction in the risk for sustained accumulation of disability. Immune thrombocytopenic purpura, thyroid adverse events, and infections occurred more frequently in the alemtuzumab groups. (Abtract #S22.006, supported by: Genzyme Corporation)
• In a special plenary session, Professor Moses Rodriguez (Mayo Clinic) described the painstaking steps his team has taken to develop a new therapy for MS and possibly other disorders using
, produced by the body’s immune system. Much of his ongoing research has been funded in part by the National MS Society. In animal models of MS, the team has found antibodies that stimulate the repair of the insulating myelin coating on nerve fibers. Myelin damage is a hallmark of MS, and its repair may improve function and protect the underlying nerve fibers. Dr. Rodriguez stated that the antibodies will soon be studied in human clinical trials.
• In a small study of 12 people takingTysabri®(natalizumab, Biogen Idec, Inc and Elan Pharmaceuticals), Dr. B. Khatri (Aurora St. Luke’s Medical Center, Milwaukee) and colleagues explored whether plasma exchange (a blood-cleansing process that involves removing and replacing the liquid portion of blood) could reduce the concentration of Tysabri in the blood and possibly serve as an intervention in case a patient develops PML, -- progressive multifocal leukoencephalo¬pathy -- a brain disease that occurred in three people (two of whom died) who had been in clinical trials of Tysabri. Tysabri concentration was decreased by 90% or more compared with levels before plasma exchange. Plasma exchange was well tolerated, with no increase in MS disease activity. All patients returned to Tysabri treatment without complications. Further study is needed to determine whether plasma exchange is an effective intervention for PML. (Abstract #S22.005, funded by Biogen Idec, Inc and Elan Pharmaceuticals)
The latest safety data on Tysabri, also presented, revealed that as of late March, 26,000 patients are now on Tysabri worldwide, and 9,900 have been exposed to drug for at least 1 year, and 3,600 exposed for at least 18 months. No new cases of PML have occurred. (Abstract #S02.002)
•Copaxone®(glatiramer acetate, Teva Pharmaceutical Industries Ltd.) significantly reduced the risk of developing MS and delayed the development of MS in individuals with CIS (clinically isolated syndrome, a first event suggestive of MS) enrolled in the PreCISe study. Dr. Giancarlo Comi presented results of this study, in which 481 people with CIS with lesions typical of MS on brain MRIs were randomly assigned to receive either Copaxone (given by daily under-the-skin injections) or inactive placebo for up to 36 months. The primary outcome measure was the time it took individuals to experience a second attack that would confirm the diagnosis of definite MS. In the Copaxone group, the risk of developing clinically definite MS was reduced by 45% versus placebo, and the time to development of definite MS was delayed by 386 days more than in the placebo group. The proportion of patients who developed MS was 43% in the placebo group versus 25% in the Copaxone group. (Abstract #LBS.003, funded by Teva Pharmaceutical Industries Ltd.) According to a press release, the company is applying to regulatory agencies for extending the labeling of Copaxone to include CIS in the U.S. and Europe.
• Dr. Paul O’Connor (University of Toronto) and colleagues reported results of the BEYOND study, evaluating the effectiveness of high and low doses (500 mcg vs. 250 mcg) ofBetaseron®(interferon beta-1b) and Copaxone. Participants numbered 899, 892, and 448 in these groups, respectively. No differences were found in the risk of relapse, the primary endpoint, or secondary endpoints such as MRI findings. The findings indicate that the currently approved dose of 250 mcg of Betaseron is the optimal dose. (Abstract #LBS.004, Funded by Bayer Schering Pharma AG)
• Dr. Emmanuelle Le Page (Hôpital Pontchaillou, Rennes, France) and colleagues administered Betaseron following treatment with
or methylprednisolone alone to 109 people with very active relapsing-remitting MS, hoping to increase the effectiveness of Betaseron with a short course of immunosuppressive treatment. Worsening disease activity as measured by the EDSS (a scale used to measure disease activity) was delayed significantly longer in the mitoxantrone/methylprednisolone group, and the percentage of patients whose EDSS score worsened by at least 1 point was reduced by 65% in this group compared with the methylprednisolone group. The annualized relapse rate was reduced by 61.5% in the mitoxantrone/methylprednisolone group, and the percentage of relapse free patients was 53% in versus 26% in the methylprednisolone group. No serious adverse events occurred during follow-up. (Abstract S22.004)
• Dr. Bianca Weinstock-Guttman (State University of New York, Buffalo) and colleagues evaluated the
that are expressed (i.e., genes that are turned on or off) in response to treatment with interferon beta. They reported that people with MS who have good clinical responses to treatment demonstrate a different pattern of gene expression responses compared with those who experienced only a partial therapeutic effect. A different profile of gene expression was also seen in patients who experienced persistent side effects to treatment. These results raise the possibility that doctors may eventually be able to determine early in the course of treatment whether a person will respond to therapy and make appropriate medication adjustments. (Abstract #S52.004, funded by the National MS Society)
Research on Tracking and Understanding MSAside from the range of clinical studies, the AAN also featured cutting-edge findings from genetics, laboratory and imaging studies. These efforts are crucial to understanding and tracking MS.
• New results were reported by Dr. Philip De Jager and colleagues in
(IMSGC), a group of international MS genetic experts created with funding from the National MS Society, who previously completed the largest replicatedwhole genome scan(scan of all the genes in the body) for MS to date, identifying two new genetic variations associated with MS. Adding 954 people with MS and 581 controls without MS to their previous study, they identified several new genetic variations associated with MS, including two genes that instruct how cells bind to each other (P Cadherin 7 and CTNNA3). Two previously identified variations were confirmed, including CD58, which instructs another cell adhesion molecule. The team is seeking to further validate findings on 5000 genetic variations with information from 1,500 people with MS and 1,500 controls without MS. (Abstract #S48.006, funded by Affymetrix Corporation)
• In other genetics news, Dr. Bruce Cree and colleagues reported on genetics studies in
. Focusing on ethnic groups with lower susceptibility to MS (such as African-Americans) and higher susceptibility (such as individuals of Northern European descent), and searching for commonalities and differences may help pinpoint chromosome regions that contain MS genes. Comparing 770 African Americans with MS and 813 whites with MS, this team identified an association in the AA population with variations in the gene that instructs the RAGE protein – different variations than had previously been identified in whites. RAGE has important immune and nervous system functions. (Abstract #S42.004, funded by National MS Society, NIH, Nancy Davis Foundation)
• For the first year ever, there was an entire poster session on
(OCT), a relatively new technique that measures the thickness of the nerve layer at the back of the eye (retinal nerve fiber layer), and can detect thinning of that layer as a possible means of tracking MS progression. Medical student Esther Bisker (University of Pennsylvania, Philadelphia) and colleagues presented results on using OCT to measure the optic disc (the head of the optic nerve) as well as retinal nerve fiber layer in 233 people with MS and 96 people without MS. The measurements were significantly different, and the group concluded that using OCT for optic disc measurements as well as retinal nerve fiber layer may help to identify eyes most at risk for nerve fiber loss. Further testing of OCT should map out its potential usefulness as a tool for tracking disease progression and as a much-needed outcome measure for clinical trials aiming to protect or repair the nervous system. (Abstract #S60.002, funded by NIH)
• Dr. Francesca Bagnato (NINDS, Bethesda, MD) and colleagues tested the safety and tolerability of a very strong
in MRI scans of 10 people with MS and 10 controls without MS. (Standard MRIs use a 1.5 tesla magnet.) So far, seven in each group have been studied and have tolerated the scan well. Transient dizziness was reported by two people with MS during table motion. The more powerful magnet allowed investigators to better visualize lesions (areas of tissue damage or disease activity), for example, differentiating between lesions with or without iron accumulation, and differentiating “substructures” within lesions, which may indicate multiple breakdowns of the blood-brain barrier. The greater contrast presents a useful tool for characterizing tissue damage in MS. (Abstract #S60.001, funded by NIH)
• Dr. Shanu Roemer and colleagues from theMS Lesion Projectexamined brain tissue obtained via biopsy from people with
for signs of inflammation in the cortex and meninges – outer membranes lining the brain. Cortical inflammation was observed in 39% of patients, and 15 of 18 available samples of meninges. (Abstract #S42.006, funded by the National MS Society, NINDS, NINDS, and Du Pres) This study follows up on previous findings fromECTRIMS 2007, in which investigators from London and Rome reported on damage in these areas in people with secondary-progressive MS.
can be a severe problem for people with MS but little is known about its cause. Dr. Robert Bermel (Cleveland Clinic Foundation) and colleagues utilized a technology called “functional MRI” to evaluate the level of activation of various parts of the brain during a motor task. They found that higher levels of MS fatigue correlated with a lower level of activation of a brain region called the thalamus. This begins to help scientists better understand the problem of fatigue in MS and may eventually lead to improved ability to treat MS-related fatigue. (Abstract #P04.161, funded by a National MS Society postdoctoral fellowship award to Dr. Bermel)
These and many other presentations reflect the rapid pace of MS research today.
Avonex is a registered trademark of Biogen IdecBetaseron is a registered trademark of Bayer HealthCare PharmaceuticalsBotox is a registered trademark of Allergan, Inc.Copaxone is a registered trademark of Teva Pharmaceutical Industries LtdRebif is a registered trademark of EMD Serono, Inc.Tysabri is a registered trademark of Biogen Idec and Elan
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