More MS news articles for April 2004
advances in MS reported at American Academy of Neurology meeting
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.
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
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
Studies in Primary-Progressive MS
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.
Long-Term Extensions of Clinical Trials
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
Early Clinical Studies
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.
Treatment of Optic Neuritis
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.
On the Horizon
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
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.
These and many other studies presented at this meeting testify to the growing
breadth and pace of research into multiple sclerosis. Followup to these
studies will help shape efforts to find new and better treatments and hopefully,
a way to restore function in those with MS.
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