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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 leukoч¬encephaloч¬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

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