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June 01, 2001
Scientists and clinicians from around the world presented results of research on multiple sclerosis research at the 53rd Annual Meeting of the American Academy of Neurology (AAN), held in Philadelphia on May 5-11. Here we present a summary of just a few of these efforts, with a special focus on clinical studies and trials of new and existing treatments. This is by no means inclusive of all MS research presented at the meeting: Out of over 1450 presentations at the conference, some 190 were related to multiple sclerosis or MS animal models.
Combination Clinical Trials
In an effort to heighten the effectiveness of therapies for MS, researchers are investigating various combinations of treatments. All of the following trials are early studies in small numbers of people. Larger studies will be needed before we will know whether these combinations are safe and are more effective in combination than they are individually.
Dr. Fred Lublin (New York) and colleagues treated 33 people with relapsing-remitting MS with Avonex and Copaxone concurrently, and found that treatment was safe (an issue that had been in question), warranting a larger trial to determine the effectiveness of this combination.
Dr. Thibault Moreau (Lyon, France) and colleagues administered Avonex and azathioprine (Imuran in the U.S.), an immune-suppressing drug, to 30 people with MS. They found the combination to be safe and tolerable, suggesting a need for additional trials to determine effectiveness. Dr. Michael Kaufman (Charlotte, NC) and colleagues enrolled 23 people who still had either relapses or progression during treatment with Avonex, and added oral cyclophosphamide or placebo. The results indicate that this combination is safe, with modest improvements in symptoms and in lessening the number of exacerbations.
Dr. Douglas Jeffery (Winston-Salem, NC) and colleagues administered Novantrone® (mitoxantrone for injection concentrate) to 7 people with MS who had been taking Betaseron® (interferon beta-1b) for at least 6 months. The combination caused no apparent adverse effects, and preliminary results suggested the frequency of new MRI-detected lesions decreased.
Other Clinical Trials
Findings were presented on several large studies extending our knowledge of the value of some currently available MS treatments. In a one-year, head-to-head trial conducted by Dr. Luca Durelli (Torino, Italy) and colleagues, 188 people with relapsing-remitting MS were randomly assigned to receive either Avonex or Betaseron. Results indicate that, during the second six months of the trial, Betaseron reduced relapse rates and reduced the appearance of new MRI-detected lesions and overall lesion activity more effectively than Avonex. The meaning of these results for longer-term clinical use is not known.
Dr. Kenneth P. Johnson (Baltimore, MD) and colleagues have followed 152 people with relapsing-remitting MS taking Copaxone® (glatiramer acetate) for 6 years, and found treatment continued to be safe and effective for a prolonged period. The investigators claim that the longer patients are treated, the more effective therapy becomes, and that delaying therapy increases the likelihood of disability.
Dr. Peter Rieckmann (Würzburg, Germany) and colleagues studied the safety and tolerability of Rebif® (interferon beta-1a) over four years in 445 people with relapsing-remitting MS. They found that the 44 microgram dose was as well tolerated and more effective than the 22 microgram dose. Using the same drug, Dr. Andrea Paolillo (Rome) and colleagues studied 55 people with relapsing-remitting MS and found that greater disease activity and MRI-detected lesion load before treatment predicted greater disease activity and brain tissue loss after 6 years of treatment – suggesting the need for early treatment.
Dr. Jeffrey Cohen (Cleveland) and colleagues presented results of the “IMPACT” study of Avonex® (interferon beta-1a) in 436 people with secondary-progressive MS. (These results were announced in a Biogen corporate press release earlier this year.) Progression of MS in the Avonex group was reduced by 27% more than placebo, and the relapse rate was reduced by 33%. In a separate study, Dr. Richard Rudick (Cleveland) and colleagues evaluated results of using Avonex in 160 people eight years after enrollment in a study relapsing-remitting MS. Those treated with Avonex from the beginning had more favorable outcomes, with less progression of disability, compared to the expected natural history of the disease and to those who had been on placebo during the trial and were then switched to active treatment at its conclusion.
Early Clinical Trials
Researchers reported on several early, smaller studies (often called pilot trials) of medicines under investigation for the treatment of MS. Such pilot studies are usually done to test new concepts or to gather preliminary data that might help a scientist to decide if a new approach should be pursued in more depth.
Dr. Rhonda Voskuhl (Los Angeles) announced the results of her pilot clinical trial in which she administered the hormone estriol (which is elevated during pregnancy, when most women experience decreases in MS activity) to six women with relapsing-remitting MS and six with secondary-progressive MS. Treatment was well tolerated, and was somewhat effective in reducing lesions in relapsing-remitting MS, although not in progressive disease. Dr. Voskuhl concluded that further study of this hormone in people with relapsing-remitting MS is warranted. This project was funded through the National MS Society’s special targeted initiative on gender differences in MS.
Several groups looked at methylprednisolone treatment, focusing on new ways of using or evaluating the use of steroids normally used to treat exacerbations of MS. Dr. Finn Sellebjerg (Hvidovre, Denmark) and colleagues found that treating MS exacerbations of 58 people with oral high-dose methylprednisolone significantly reduced MRI-detected disease activity. They also found that people who had active lesions at entrance into the study had a greater response to oral therapy. Dr. Tania Kümpfel (Munich) and colleagues found that monthly treatment with intravenous high-dose methylprednisolone (IVMP) reduced the number of active lesions by 49% in a group of 10 people with MS. Dr. Robert Zivadinov (Trieste, Italy) and colleagues found that IVMP every four months slowed brain tissue loss and the progression of disability in 81 people with relapsing-remitting MS. Dr. Joseph Frank (Bethesda, MD) and colleagues also found that IVMP to treat exacerbations decreased MRI-detected lesions for up to two months following treatment.
Valacyclovir is an antiviral medicine that is under investigation because of studies suggesting a possible association between herpes viruses, particularly HHV-6, and MS. Two separate teams of investigators (from Århus, Denmark and New York, NY) tested valacyclovir in groups of people with relapsing and progressive forms of MS. Neither showed significant benefit on symptoms in most participants. One study found a subgroup of people with high disease activity (determined by MRI) when enrolled in the study in whom new lesion formation appeared to be reduced by the treatment. It is not clear, based on these studies, whether this drug holds potential to treat MS.
Dr. Arthur Vandenbark (Portland, OR) and colleagues administered a vaccine to alter immune cell activity, known as a “T-cell receptor peptide” vaccine, or placebo, to 106 people with relapsing-remitting MS. They found that the treatment was safe and well tolerated, and that immune cell activity was altered in a way that could suggest benefit in approximately one-half of those receiving the vaccine. Further studies are planned.
Dr. Michael J. Olek (Boston) and colleagues studied interferon tau in a group of 31 people with relapsing-remitting MS. This immune system molecule is similar to other interferons but is administered orally, and has been shown to have fewer side effects in rodent models of an MS-like disease. Dr. Olek reported no significant side effects, and is planning to study the drug’s effectiveness in 100 people with relapsing-remitting disease.
Characterizing Primary-Progressive MS
Researchers presented studies on primary-progressive MS, which involves a progressive course at onset without prior relapses. Dr. Giuseppe Santuccio (Milan, Italy) and colleagues studied people with primary-progressive MS in comparison to people with secondary-progressive MS (in which people begin with a relapsing course and change to a more progressive course later). They found less MRI-detected lesion activity in people with primary-progressive MS than secondary-progressive MS, but found more brain tissue damage in primary-progressive MS, as detected by novel imaging methods. They also found that the extent and severity of damage to the spinal cord in the neck area (“cervical” cord) is a main factor leading to disability.
Dr. Daniel Pelletier (San Francisco), a Sylvia Lawry Physician Fellow of the National MS Society, presented results on a study of nerve tissue damage in 23 people with primary-progressive MS, detected by brain imaging. They found that the loss of brain tissue overall in these people did not correlate well with areas of myelin (nerve fiber insulation) loss, indicating that the underlying mechanisms leading to brain tissue loss and myelin loss may differ.
Clinical and Laboratory Studies
Results of many basic studies related to multiple sclerosis were also reported at the meeting. Dr. Guy J. Buckle (Boston) and colleagues found that immune cells called CD8+ T cells are activated in people with secondary-progressive MS. These cells secrete a molecule, lymphotoxin, that has been shown to cause myelin damage, so this may explain the chronic destruction of myelin seen in people with this type of MS.
Four research teams presented findings related to a possible role for the bacterium Chlamydia pneumoniae and multiple sclerosis. Several found some evidence of elevated immune system response to the bacterium, but no direct evidence that it plays a causative role in MS. An estimated 90-95% of the population has been exposed to this bacterium, and work to uncover a possible role of Chlamydia pneumoniae in MS continues.
Dr. Dorothee E. Chabas (Stanford, CA) and colleagues found that a molecule capable of aiding inflammation, called osteopontin, was abundant in samples of MS brain lesion tissues. In mice genetically engineered to lack this molecule, progressive MS-like disease rarely developed. The researchers concluded that osteopontin may be critical to the immune attack in MS, and may present a promising target for developing new therapies.
Dr. Wei-Ping Li (Newark, NJ) and colleagues, in a study funded in part by the National MS Society, found that several molecules known as caspases may be involved in the cascade of events leading to the death of myelin-making cells. The investigators suggest that in the future, the death of myelin-making cells in MS may be blocked by compounds that selectively inhibit the caspases involved.