http://www.nationalmssociety.org/Research-2004Apr28_b.asp

April 30, 2004
The National Multiple Sclerosis Society

Neurologists and neuroscientists from around the world gathered to share their research findings at the American Academy of Neurology’s 56th Annual Meeting in San Francisco April 24 to May 1, 2004. Following are selected highlights from over 200 presentations that had relevance to multiple sclerosis.

During the meeting, the 2004 John Dystel Prize for Multiple Sclerosis Research was awarded to Professor Lawrence Steinman of Stanford University, an innovative neuroimmunologist who has contributed much to our understanding of MS, and who has translated his findings to develop therapeutic strategies that are already under study in people with MS. Details about Dr. Steinman’s outstanding contributions are available here.

Clinical Trials

Results from a study of the oral immune-modulating drug laquinimod were presented by Dr. Magnhild Sandberg-Wollheim (Lund, Sweden) on behalf of colleagues in Amsterdam and Sweden. The placebo-controlled, early phase trial of two doses of the agent was conducted in 209 persons with relapsing forms of MS. The drug was well tolerated, and those on the higher dose had significantly fewer new active MS brain lesions during the 24 weeks of testing. Larger studies are needed to further explore the drug’s potential to help those with relapsing MS.

• Dr. John Rose (VA Medical Center, Salt Lake City) and colleagues reported on a small, open-label clinical trial of Zenapax® (daclizumab), an immune-modulating drug given by monthly intravenous (into the vein) infusions. So far their results in 16 individuals suggest that the drug may stabilize or even improve the clinical status of individuals with relapsing-remitting and secondary-progressive MS who had not benefited from other therapies. Zanapax is a monoclonal antibody that inhibits the ability of the messenger chemical, interleukin 2, to stimulate destructive immune activity. The authors note that the potential of this drug is being explored, alone and in combination with other immune-modulating drugs, in a Phase 2 clinical trial.

• There are ongoing efforts to determine whether killing individuals’ immune cells and reconstituting them with immune stem cells derived from their own blood or bone marrow (a procedure called autologous hematopoietic stem cell transplantation, or bone marrow transplantation) can stop MS. Dr. Mark Freedman (University of Ottawa, ON, Canada) and other members of the Canadian MS/Bone Marrow Transplant Study Group presented findings from their ongoing efforts involving persons with early, aggressive forms of MS. This group used chemotherapy to kill immune cells before transplant. Preliminary results reported previously suggested that most who underwent the procedure stabilized and had no new brain lesions seen on MRI.


To track whether signs of myelin destruction and repair had been impacted by the procedure, the investigators analyzed MRI scans before and one year after the transplants in five individuals, using a technique called magnetic transfer ratio. Scans taken before transplant showed signs of active myelin destruction and myelin repair. Scans taken one year after the transplants revealed major reductions in both myelin destruction (a potentially beneficial outcome) and myelin repair processes (a potentially negative outcome). The group also presented initial evidence that the transplant procedure might result in the reformation of a “new” immune system in those whose immune responses were erased by the chemotherapy treatments. Further trials, which are ongoing, will hopefully sort out issues such as which is the safest protocol and who might best benefit from this high-risk and expensive procedure.

• Investigators from the University of California, Los Angeles, led by Dr. Rhonda Voskuhl, had conducted a small clinical trial of the pregnancy-associated hormone estriol in 10 women with MS and had previously reported finding beneficial signs on immune activity and brain lesion activity in those with relapsing-remitting MS. To further explore results in terms of whether estriol can protect nerve tissue, the investigators, whose work was funded in part by the National MS Society, conducted further analyses of the MRI scans taken before, during and after treatment during the trial. They examined any changes in “black holes,” which are lesions thought to show damage to nerve fibers.


Among their findings, the investigators reported that the rate of accumulation of black holes slowed during treatment in women with relapsing-remitting MS. The investigators suggest that estriol may have nerve-protecting benefits, in addition to the hormone’s impact on immune activity. More studies will be needed to confirm these findings and also to confirm the safety and efficacy of estriol therapy for MS.

• Dr. Mariko Kita of Virginia Mason MS Center in Seattle, and colleagues across the country, conducted a Phase 2 clinical trial of Novantrone® (mitoxantrone) to treat primary-progressive MS, a less common form of MS that involves steady progression of disability from onset and for which there is no currently approved therapy. The study involved 61 individuals, half of whom received inactive placebo and half received intravenous infusions of Novantrone every three months for up to 24 months. Dr. Kita presented the disappointing results, which showed that there was no apparent clinical benefit in any of the clinical outcomes studied. MRI analysis of lesion changes in the brain are still ongoing.

• A large-scale clinical trial of Copaxone® (glatiramer acetate) for treating primary-progressive MS (the “PROMiSe” Trial) was stopped prematurely in 2002 because an interim analysis of the data indicated that the trial could not show a benefit of Copaxone over placebo, even if continued to its intended completion date. Data from the trial were presented by Dr. Jerry S. Wolinsky (University of Texas Health Science Center). The investigators found that on the pre-established primary endpoint (the time it took for participants to progress using the EDSS scale), no significant clinical benefit was seen over placebo.


Further analysis suggested that males on Copaxone showed a statistically significant reduction in progression and in some measures of MRI-detected brain lesions, and that participants overall showed a “trend” toward  slowed progression, although this was not statistically significant. Further research would be required to determine whether Copaxone can benefit some individuals with primary-progressive MS.

• Further analyses from a clinical trial support the potential of the oral medication Aricept® (donepezil hydrochloride, Pfizer, Inc.) to modestly improve performance on memory tests in individuals with multiple sclerosis. (At last year’s AAN meeting Dr. Lauren B. Krupp and colleagues at State University of New York, Stony Brook had reported findings from their investigation of whether this drug, which is used to improve memory in Alzheimer’s disease, could also help those with MS.) The 35 persons on Aricept for 24 weeks showed significantly greater improvements on some memory tests, and in clinician and patient reports, than 34 subjects taking inactive placebo. The study did not examine the extent to which improvement in memory might have had an impact on everyday activities. Larger studies are needed to confirm the safety and benefits of this medication for improving memory in MS. At least one such study is in planning stages.

• Investigators from the U.S. and Canada presented results of the “CHAMPIONS” study, an open-label extension study that followed original participants of the two-year “CHAMPS” study. The CHAMPS study had successfully shown that Avonex® (interferon beta-1a), given to individuals who had experienced their first clinical demyelinating event (a single attack of a neurological symptom), could slow the development of definite MS compared to placebo. As a followup, the CHAMPS participants were offered a chance to switch from placebo to treatment, or continue on treatment, until five years had elapsed since the start of the original study.


The CHAMPIONS study compared outcomes in those who had gotten drug from the start of the CHAMPS study (“immediate treatment” or IT group) versus those who had switched from placebo after about 30 months (“delayed treatment” or DT group). Dr. R. Philip Kinkel (Harvard’s Beth Israel Deaconess Medical Center) presented the findings, showing that the IT group (100 individuals) had significantly fewer relapses and fewer MRI brain lesions than the DT group (103 individuals), and that significantly fewer of its members converted to definite MS. The investigator  noted that these findings offer further support for the idea that initiating disease-modifying therapy early in those at high risk for developing MS may have a long-term benefit. The investigators plan to continue following participants in the future.

• Dr. Kenneth P. Johnson (University of Maryland, Baltimore) and colleagues across the country have been following the long-term outcomes of individuals who participated in the original, multicenter, placebo-controlled clinical trial of Copaxone® (glatiramer acetate) which led to its approval for relapsing-remitting MS. After the original trial, an “open label” study began in which participants were given the choice to continue taking the drug (or switch from placebo to active treatment).


The team compared the progression of disability after 10 years between 108 participants who had been on treatment continuously since the start of the original trial and 47 who withdrew from the open label study after several years but who were followed even if not using the agent. The investigators reported that those who had been on continuous treatment showed significantly less progression of disability than those who had withdrawn, and suggested that Copaxone is effective over many years. In spite of this positive indication of long-term benefit, the lack of information on the outcomes of the 77 patients who withdrew from the study and were lost to followup, and the lack of data concerning why many of the individuals withdrew from the study, complicate the interpretation of these findings.

• A small, placebo-controlled safety study of alpha lipoic acid (an antioxidant) was conducted by Drs. Vijayshree Yadav, Dennis Bourdette and others (Oregon Health & Science University). Thirty volunteers with relapsing or progressive MS received one of two doses of alpha lipoic acid or inactive placebo for two weeks. This study did not test for a clinical benefit, but the treatment seemed to be well tolerated. By examining the blood of participants the investigators noted that some who took alpha lipoic acid had lower serum levels of an enzyme – matrix metalloprotease-9 – which is thought to aid the movement of disease-causing immune T cells into the brain and spinal cord. The investigators suggested that more clinical studies of alpha lipoic acid in MS are warranted.

• An international team of investigators is involved in the MS Lesion Project, a National MS Society-supported effort to find links between types of damage in the brains of individuals with MS and patterns of destructive immune factors. The team, led by Dr. Claudia Lucchinetti (Mayo Clinic), reported a new finding related to an analysis of lesion patterns in a small number of individuals who had received plasma exchange therapy, a blood-cleansing technique that has been used for severely progressive MS. Dr. Mark Keegan showed that those patients whose lesion pattern (“pattern II”) included immune proteins known as “antibodies” were responsive to plasma exchange therapy, while those without such a lesion pattern were not responsive. These data provide further evidence for the possibility that different patterns of MS tissue damage in the brain may be responsive to different kinds of treatments.

• A small, placebo-controlled trial by Danish investigators sought to determine whether multiple doses of intravenous immunoglobulin (IVIG) treatment, initiated within 30 days of onset of optic neuritis (an eye condition that is often the first symptom of MS), could improve visual symptoms six months after the initial onset. Dr. Hanne G. Roed (Hvidovre, Denmark) and colleagues found that after 6 months, there was unfortunately no detectable difference in the duration of optic neuritis or other visual outcomes between the 34 participants who were on drug versus the 34 on inactive placebo, suggesting that for this condition, IVIG may not provide benefit.

• For as long as 31 years, Swedish investigators have been following a group of individuals who had had a single episode of optic neuritis and were at risk for developing definite MS. Although this eye disorder can be the first symptom of MS, it can also remain an isolated episode which never develops into MS. Drs. Magnhild Sandberg-Wollheim, Roland Perfekt and others from the University of Lund have been following members of this group to seek characteristics that might help determine risks for developing definite MS.


Overall, after 15 years, there was only a 40% chance of developing definite MS, most of which occurred within 3 years of the first optic neuritis episode. One factor at onset of optic neuritis that was particularly telling was evidence of inflammation in the spinal fluid; in such cases, individuals had a 49% chance of developing MS, versus a 23% risk among those with normal spinal fluid. The researchers observed that the relatively low overall risk for developing MS among individuals with a first episode of optic neuritis, even in those with MRI-detected lesions, should be taken into account by physicians in deciding whether early treatment of a single episode of optic neuritis is warranted.

• Drs. Tamir Ben-Hur (Hadassah-Hebrew University Hospital, Jerusalem), Jeff Bulte (Johns Hopkins University) and colleagues reported success using available human embryonic stem cells to explore their potential to help repair nervous system damage in rodents with multiple sclerosis-like disease. The investigators used both mouse and human embryonic stem cells to create nerve cell precursors for transplantation into the brains of mice and rats with the MS-like disease, EAE. They magnetically “tagged” the cells and then used MRI to determine that the cells, with inherent potential to develop into functional nervous system cells, moved into the brain lesion sites where tissue had been damaged. This project helps validate the utility of a non-invasive means of tracking cell movement in the brain and thus may become an important tool for future research in tissue repair. It also takes a further step in the process of determining the potential of stem cells to assist in tissue repair in MS.

Copyright © 2004, The National Multiple Sclerosis Society