Positive Clinical Trial Results Take Center Stage At American Academy Of Neurology Meeting

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 this country’s top 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. This summary covers just a fraction of the platform talks. To read the researchers’ original abstracts, sign up at no charge at the American Academy of Neurology’s Website.

During the meeting, this year’s winner of the National MS Society/American Academy of Neurology’s John Dystel Prize for Multiple Sclerosis Research was announced. Professor David H. Miller, MD, FRCP (Institute of Neurology, University College London) revolutionized what we know about MS and its treatment through his pioneering research using imaging techniques such as magnetic resonance imaging (MRI).

Presented in abundance at the meeting were short-term and long-term studies of the currently approved disease-modifying therapies for MS, which generally continue to show benefits and sometimes unsuspected mechanisms of action. But taking center stage at this year’s meeting were the first public presentations of positive results from two phase 3 clinical trials of experimental oral therapies for relapsing MS: cladribine and fingolimod.

Experimental or Approved Therapies

– Cladribine: Results from the CLARITY study of oral cladribine in 1326 people with relapsing-remitting MS were presented for the first time by Gavin Giovannoni, MBBCh, PhD (Queen Mary University London and Barts and The London NHS Trust). The study was sponsored by Merck Serono. Cladribine is a chemotherapy that kills immune T cells and B cells, both of which are thought to be involved in immune attacks in MS. After 96 weeks (nearly 2 years), the “annualized” relapse rate in those on cladribine was reduced by 54.5 to 57.5%, depending on the dose, compared to those on placebo. (For this primary endpoint of the study, those on placebo had an average of 0.33 relapses per year, versus 0.14 or 0.15 for those on therapy.). About 80% of those on cladribine were relapse-free over the two years, versus about 60% of those on placebo. Both doses of cladribine also produced significant reductions in disease activity detected with MRI, and reduced the risk of disease progression by about 32% relative to placebo. Data about the drug’s impact on loss of brain tissue (atrophy) has not yet been analyzed.

In terms of safety, Dr. Giovannoni reported that 8.7% of those on cladribine experienced serious adverse events, versus 6.4% of those on placebo. There were 5 cases of different types of cancer among the 889 people who were on active therapy, and one of the main side effects experienced by those on active therapy was deficiency of white blood cells (lymphopenia), which might be expected from this type of agent and which would probably require monitoring if the drug becomes an approved therapy. A company press release suggested that they would apply for the drug’s marketing approval later in 2009. (Abstract LBS.001)

– Fingolimod: Jeffrey Cohen, MD (Cleveland Clinic) presented first results of the Novartis-sponsored TRANSFORMS study that compared two different doses of oral fingolimod (FTY720) with Avonex® (interferon beta-1a, Biogen Idec) over only one year. The study randomly assigned 1292 people with relapsing-remitting MS who had experienced one or more relapses over the previous year (or two relapses in the previous two years) into one of three groups: Avonex, lower dose fingolimod, or higher dose fingolimod. Those taking the lower dose of fingolimod had 52% lower relapse rates after one year than those on Avonex, and 80 to 83% of those on either dose of fingolimod remained relapse-free over the year, compared to 69% of those on Avonex. The effect of fingolimod on longer term disability progression was not evaluated.

Adverse side effects seen more often in the treatment groups included temporary reductions in heart rate at the start of therapy, small increases in blood pressure, and a few cases of macular edema (swelling of the back of the eye). Two deaths from herpes infections occurred in the group taking the higher dose of fingolimod, and seven cases of localized skin cancer occurred in the fingolimod groups. Several longer phase 3 clinical trials are currently underway, including one involving people with primary progressive MS; these additional studies should help clarify whether the adverse events were related to the experimental treatment. A company press release suggested that they plan to apply for the drug’s marketing approval at the end of 2009. (Abstract S21.004)

– 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

– Smoking: Joseph Finkelstein, MD, PhD (Johns Hopkins) and colleagues, in collaboration with the Baltimore VA’s MS Center of Excellence, reported on a study using the 2002 National Health Interview Survey of over 30,000 households. A small proportion of those surveyed told interviewers that they had been diagnosed with MS. The cigarette smoking history of these 87 people was compared to that of 435 matched controls who did not have MS. The investigators found that people who had started smoking early (prior to age 17) were 2.7 times more likely to develop MS, versus those who started smoking later or never smoked. It is not clear whether other behavioral factors contributed to the increased risk of MS in this relatively small sample of individuals. This study adds to the growing body of information related to cigarette smoking and its apparent contributions to MS susceptibility and progression. (Abstract S01.001)

– Breastfeeding and MS: A quandary facing women with MS and their doctors relates to a crucial time period after giving birth, when there is a higher risk for relapse, and many women are advised to go back on their disease-modifying therapies as soon as possible. Since there is insufficient evidence to support the safety of breastfeeding while using any of these therapies, most babies born to moms with MS are bottle fed, despite known health benefits of breastfeeding for infants.

Annette Langer-Gould, MD, PhD (Stanford University) and colleagues conducted a pilot study in which they followed 32 pregnant women with MS and a matched set of pregnant women without MS, assessing their disease and breastfeeding status at intervals out to 12 months after giving birth. In this small sample, they found that women who breastfed their babies exclusively (without giving supplemental bottles) for at least the first two months post-partum were five times less likely to have an MS relapse than those who did not breastfeed or who did not breastfeed exclusively during the first two months.

The investigators suggest that the results may be biased because women in their study with more severe MS were less likely to breastfeed, while those with milder MS were more likely to breastfeed. Nevertheless, this study points to the importance of this issue; more research is needed to help guide postpartum treatment decisions. (Abstract S01.006)

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)

National MS Society

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