More than 11,000 neurologists, investigators and trainees gathered in Seattle in late April for the 2009 annual meeting of the American Academy of Neurology, one of the most important venues for sharing clinical research progress related to multiple sclerosis and other neurological disorders. This year, there were over 400 platform and poster presentations focusing on progress related to MS.
DETAILS
New and existing treatments
Mitoxantrone: The American Academy of Neurology spotlighted two late-breaking studies for their potential impact on clinical practice. One, by Vittorio Martinelli, MD (University Vita-Salute, Milan) and colleagues across Italy, found a higher than expected incidence of acute leukemia occurring in people with MS who had been treated with mitoxantrone. Previous studies had identified the risk of heart damage, and had also found that leukemia occurred in 0.07 to 0.25 percent of people with MS taking this drug; this study found a higher incidence of leukemia: 0.74 percent. The investigators went back to records of 2854 individuals who had been treated with this therapy. Those who developed leukemia did so after an average of 18 months after ending therapy, and received a greater number of administrations than those who did not develop leukemia (8.6 cycles, versus 7.2 cycles) and higher cumulative doses (82.4 mg/m2 versus 62.87 mg/m2). The investigators conclude that those treated with mitoxantrone should be monitored for signs of leukemia, and that this risk should be weighed against potential benefits. (Late Breaking Abstract LB3.001)
Add-on Steroids: The second study spotlighted by the Academy was the MECOMBIN study, a controlled clinical trial by Mads Ravnborg, MD (Copenhagen University Hospital) and international collaborators that was sponsored by Biogen Idec. It involved 341 people with relapsing-remitting MS who had never received disease-modifying therapy before. All were started on weekly Avonex (interferon beta-1a) injections, and half of them also received monthly doses, or pulses, over three days of the oral steroid methylprednisolone or placebo pills over three years. The primary outcome measure, time to disease progression sustained over six months, was not statistically different in the two groups after three years, but there were statistically significant differences in those on both therapies for some secondary outcomes, including a 38 percent reduction of relapse rates and better outcomes on the MSFC, a scale used to test physical and cognitive functions. They reported no unexpected side effects. (Late Breaking Abstract LB3.002)
Rituxumab: A two-year, phase 3 trial of intravenous rituxumab (Genentech Inc and Biogen Idec) in 439 people with primary progressive MS was previously announced to have shown no pronounced benefit based on its primary measurements. However, the study was designed to tease out effects in subgroups of patients, and Kathleen Hawker, MD (Ohio State University) and colleagues described results from these further analyses. They found that disease progression was significantly delayed in participants who were less than 51 years of age and in those whose pre-treatment MRIs showed signs of active (gadolinium-enhanced) brain lesions indicative of inflammation. This benefit was more pronounced in people younger than 51 with active brain lesions. The investigators conclude that these results will inform the design of future trials involving people with primary progressive MS. (Abstract S21.003)
Natalizumab: Carmen Bozic, MD (Biogen Idec) presented the latest usage and safety statistics for Tysabri (Biogen Idec and Elan Pharmaceuticals), which in the U.S. is approved for administration to people with relapsing-remitting MS through the TOUCH risk management program. As of the end of March 2009, 40,000 people worldwide were being prescribed Tysabri. Since Tysabri was reintroduced to the market in July 2006, 24,900 people have been on it for at least one year; 14,400 have been on it at least 18 months, and 6,800 have been on it for at least two years. As of the end of April 2009, there have been six confirmed cases of PML (progressive multifocal leuko¬encephalo¬pathy) since its reintroduction to the market; the companies estimate the rate of PML to be 1.2 cases per 10,000 users overall (compared with the original estimate of 1 in 1,000).
Through the TYGRIS safety study, which has enrolled over 5,000 users worldwide, the companies continue to monitor the incidence of adverse events. In addition, several ongoing clinical studies are underway to further characterize Tysabri’s impacts on MS fatigue and other clinical and quality of life issues. (Abstract S11.005)
Treating MS symptoms Ginseng for MS fatigue: Edward Kim, MD (Oregon Health & Science University) presented findings of the first controlled clinical trial testing the ability of American ginseng to control MS fatigue, which was sponsored by the National MS Society and other funders. Most of the tests used to detect an impact over 6 weeks of use showed no apparent benefit in 56 individuals with different types of MS. Among possible side effects noted were headache, rash, and diarrhea. (Abstract S21.006)
Memantine for MS cognitive problems and spasticity: Jesus Lovera, MD (Louisiana State University) and collaborative partners from other institutions across the U.S. conducted a controlled clinical trial of the Alzheimer’s drug memantine involving 126 people with different forms of MS and cognitive impairment; 68 were randomly assigned to the placebo group and 58 to the treatment group. After three months, there was no benefit noted for those on active treatment. (Abstract S11.002). A related study by National MS Society Sylvia Lawry Fellow Lahar Mehta, MD, and colleagues at the University of Rochester also found no benefit in the use of memantine for the treatment of MS-related spasticity (Abstract P07.138)
MS in Children
Antibodies: The presence of immune antibodies in the spinal fluid is among signs doctors look for when they are diagnosing MS, but not everyone who has MS has these antibodies, which are called “oligoclonal bands.” In their first platform presentation as research collaborators, Dorothee Chabas, MD, PhD, and other members of the National MS Society’s six Pediatric MS Centers of Excellence shared results of a study comparing spinal fluid characteristics of 82 children diagnosed with MS before and after age 11. The spinal fluid was analyzed within the first three months of disease onset. The investigators found that a significantly lower proportion of those with onset before age 11 had oligoclonal bands in their spinal fluid, and tended to have lower amounts of a key antibody (IgG) than those who were older at disease onset. They also found higher levels of white blood cells called neutrophils. The team points out that these features, which are less like MS in adults, should be taken into consideration when children are being diagnosed. (Abstract S01.003)
MS Risk Factors
Genes Influencing MS Progress in understanding the influence of genes on MS susceptibility and disease course was apparent from several platform and poster presentations.
MS susceptibility genes: Trevor Kilpatrick, MB, BS, PhD, FRACP (University of Melbourne) reported on a large-scale gene scan supported by MS Research Australia and the Australian Research Council. They compared genetic material from 3,874 people with MS and 5,723 people without MS in search of gene variations that appeared to make people more susceptible to developing the disease. They confirmed 6 gene variations that had been previously identified, and found 15 variations not previously reported. These include a region on Chromosome 12 that has also been associated with autoimmune diseases such as rheumatoid arthritis and type 1 diabetes, further confirmation that at least some of the same gene variations may be at work in MS and other immune diseases. (Late Breaking Abstract LBS.003)
Protective genes: Gabriele DeLuca, MD, PhD (University of Oxford) and international collaborators presented results suggesting that a specific gene variation may confer protection against severe MS. The investigators explored genetic material from 241 individuals who had experienced only one symptom – visual loss (due to optic neuritis) – but never went on to develop definite MS. They compared their genes to those of hundreds of individuals who had definite MS, including some with either benign or severe disease courses. Among their findings, their study confirmed that significantly fewer people who had a severe course had a previously identified MS gene (HLA-DRB1*01) related to immune activity, suggesting it is protective against the development of MS. The investigators note that research into its protective mechanism may provide important new avenues for treatment. (Abstract S17.002)
Clues from Imaging Studies Role of glutamate: A large study supports the possibility that excess amounts of glutamate in the brain may contribute to progressive tissue damage in MS. Glutamate helps excite nerve cells, and some research suggests that too much glutamate may contribute to tissue damage in MS. In a study funded by the National MS Society to test the relationship of this chemical to tissue loss, Daniel Pelletier, MD (University of California, San Francisco) and colleagues did annual MRS (magnetic resonance spectroscopic) scans in 265 people with early or established relapsing-remitting or secondary-progressive MS. MRS can detect quantities of chemicals in different parts of the brain; one chemical called NAA is considered a marker that goes down as nerve tissue is injured.
The researchers found that, in the gray matter of the brain where nerve cell bodies reside, the higher the level of glutamate, there was a corresponding loss of NAA, indicating nerve damage. This was not observed in the white matter, which contains the nerve fibers that are covered by myelin. These findings provide further evidence of a link between glutamate and nerve tissue loss in MS. (Abstract S31.002)
Predicting progression: Having better tools that can help measure the effectiveness of new therapies and help predict whether MS will progress over time is an important goal of clinical researchers. To help address this need, Elizabeth Fisher, PhD (Cleveland Clinic) and colleagues conducted a study, supported by the National Institutes of Health, that used MRI measures to follow the course of 63 individuals with relapsing-remitting or secondary-progressive MS for an average of 6.5 years. They compared their imaging findings to clinically measured disease progression using MSFC, a scale used to test physical and cognitive functions. They reported that MRI measures of brain shrinkage, or atrophy, were the best predictors of future clinical worsening measured by the MSFC, but they did not correlate with changes in the more traditional measure of disease progression, the EDSS. Work is underway to further enhance the MSFC as a sensitive measure of disability. (Abstract S31.004)
With Information from the National MS Society
National Research and Programs
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