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Research News from ACTRIMS –
Americas Committee for Treatment and Research in Multiple Sclerosis,
October 3, 2004
The ninth annual meeting of the Americas
Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS)
focused on progress being made in MS research. The day-long
program enabled nearly 200 specialist physicians, basic scientists
and clinical investigators to exchange a wide variety of information
and discuss research findings in order to speed the pace of
scientific discovery and improve care for people with MS.
This year’s meeting of ACTRIMS was
held in Toronto on October 3, immediately preceding the American
Neurological Association's annual conference. The meeting was
chaired by Dr. Jerry S. Wolinsky and jointly sponsored by the
National Multiple Sclerosis Society (USA) and the University
of Maryland School of Medicine, in collaboration with the Multiple
Sclerosis Society of Canada.
Following are highlights from the ACTRIMS
2004 program. In addition, the abstracts are posted on the ACTRIMS
website. (English only)
Ethical Issues in MS Clinical Trials
In the keynote address, National MS Society
Chief Medical Officer Dr. Aaron Miller (Mount Sinai School of
Medicine, New York, NY) discussed the ethics of testing MS drugs
against inactive placebo. In placebo-controlled studies, an
inactive placebo is administered to a “control”
group to compare against the benefits and liabilities of a test
drug, while keeping as much as possible about treatment administration
and monitoring “common” between the active and placebo
groups. These studies are widely acknowledged as the most efficient,
cost effective, and decisive means of testing the safety and
effectiveness of a therapy.
However, since the approval of the first
treatment for relapsing forms of MS in 1993, and with the approval
of additional agents in subsequent years, debate has been ongoing
about whether placebo-controlled trials are still ethical and
practical in people who have forms of MS for which there are
approved treatments.
Dr. Miller cited the conclusions of a National
MS Society Task Force in 2001 that placebo-controlled studies
are only ethical for 1) forms of MS where treatments are widely
available but the participants have actively declined the use
of those treatments; or 2) for individuals who have forms of
MS for which there are no approved or available treatments.
These circumstances can make recruitment for clinical trials
very difficult.
Dr. Miller noted some options to placebo-controlled
studies, such as using other drugs as controls, or studying
drugs in combinations with approved agents. “The desire
to achieve better treatment for MS is strong, yet the ethical
requirement for the protection of individuals remains paramount,”
said Dr. Miller. He noted in conclusion that a major step in
addressing these issues will be taken when the National MS Society
convenes a workshop on this and other topics related to clinical
trials in MS in December 2004.
Multiple Sclerosis Pathological Subtypes
Much work is taking place in laboratories
around the world to study the pathological subtypes of MS. If
the reasons for these differences can be determined, this is
the case, then therapies might be better targeted based on the
subtype. Four leading researchers reported on progress to date.
MS Lesion Project Update
Dr. Claudia Lucchinetti (Mayo Clinic, Rochester, Minn) presented
an update of the National MS Society-funded MS Lesion Project,
an international collaborative effort to determine how clinical
symptoms, imaging findings, and pathology correlate in people
with MS. To date, tissue samples have enabled the group to classify
286 people with MS as having one of four patterns of lesions
(areas of damage to nerve-insulating myelin), each pattern appearing
to have different causes of destruction. Dr. Lucchinetti reported
that the pathology of several severe diseases similar to MS
– neuromyelitis optica (NMO) and Balo’s concentric
sclerosis – correlate with specific lesion patterns, and
the team found a molecule in the blood that reliably distinguished
NMO from MS. These findings, which are to be published in an
upcoming issue of the scientific journal Lancet, further confirm
the ability of this extensive project to improve the diagnosis
and treatment of MS.
Immunology Correlates of MS Subtypes
Dr. Richard Ransohoff (Cleveland Clinic Lerner College of Medicine,
Cleveland, Ohio) reported on a project which examined the immunology
of lesion patterns described by Dr. Lucchinetti. The research
group have focused in particular on patterns two and three which
were found in 84% of people with MS in the study. The work looked
at the expression of chemokines, substances that have a well-known
role in inflammation within the immune system. They found that
although there are similarities in immune function between pattern
one and three, there are also striking differences. This research
supports the theory of different lesion patterns in their immunology
as well as in pathology, imaging results and clinical symptoms.
MRI Correlates
Dr. Wayne Moore (University of British Columbia) reported on
several non-standard MRI techniques that are promising to yield
greater information about how and why MS lesions develop. Dr.
Moore’s research is supported by the MS Society of Canada.
For example, magnetic spectroscopy (MRS) can measure biochemical
markers and is useful for determining damage to axons (nerve
fibres) in the MS process. He also reported on work using another
technique called diffusion weighted imaging (DWI) which is being
used to study so-called normal appearing white matter in which
standard MRI has not found MS lesions. The research group has
found by using DWI they can detect abnormalities including both
myelin and axonal loss. By examining early damage, the researchers
hope to learn more about how MS progresses.
Significance of Pathologic Classification
Systems
Dr. Samuel Ludwin (Queen’s University, Kingston, Ont.)
addressed the question of the usefulness of developing pathologic
classifications systems for MS lesions. He noted that in recent
years it has become clear that most pathological classifications
have concentrated on the acuity of the process. Although the
efforts by Dr. Lucchinetti and her colleagues represented the
first real attempt to develop a classification system based
on pathogenesis, there is a real need for classifications based
on real time imaging studies with pathological confirmation.
Such classifications would also have to go beyond descriptions
of demyelination and inflammation. They must take into consideration
the degree of axonal damage, and damage to the normal appearing
white matter and cortex, in order to be of use clinically, predictively
and therapeutically.
Tracking Nerve Stem Cells
Dr. Jeff Bulte (Johns Hopkins University
School of Medicine, Baltimore) is testing the capabilities of
nerve stem cells (immature cells capable of forming brain cells)
using a cutting-edge, non-invasive method, with funding from
a National MS Society Pilot Research Award and a grant from
the National Institutes of Health. His team labelled mouse brain
cells with a magnetic probe, then injected them into the brains
of mice with the MS-like disease EAE, and tracked them using
magnetic resonance imaging. Dr. Bulte reported further on results
originally presented at the annual meeting of the Academy of
Neurology in the spring of 2004, noting that most movement or
migration of the injected cells occurred early during active
disease, and greater migration occurred when disease was more
severe. This study provides important data on the timing of
such cell replacement therapies, and on the capabilities of
cells to migrate to areas of damage. Much further study is necessary
in such models before human trials can be undertaken.
Results Presented from Phase Two
Fampridine Study
Dr. Andrew Goodman (University of Rochester,
NY) and colleagues reported the results of a study of fampridine-SR
(a slow-release formula of 4-aminopyridine being developed by
Acorda Therapeutics) to treat MS symptoms. Fampridine-SR blocks
tiny pores, or potassium channels, on the surface of nerve fibres,
and thus may improve the conduction of nerve signals in nerve
fibres whose myelin coating has been damaged by MS. In a double-blinded
placebo-controlled dosing study, 206 people with MS were randomized
to receive either fampridine 10 mg, 15 mg, or 20 mg, or inactive
placebo for 12 weeks. The results indicate a trend (an effect
which does not quite reach statistical significance) toward
improved walking speed in the fampridine groups, and a significant
increase in leg strength. Side effects included dizziness, insomnia
and nausea, with two people in the 20-mg group having seizures
(one from an accidental overdose). Further study is needed to
determine the safety and effectiveness of this drug for MS.
Oral Pirfenidone for Secondary-Progressive
MS (Poster presentation)
Dr. Jonathan Walker and colleagues (University
of Texas Southwestern School of Medicine) tested the safety
and effectiveness of the experimental, oral drug pirfenidone
in a small number of people with secondary-progressive MS. Among
its actions, pirfenidone inhibits the immune messenger protein
TNF-alpha. Twenty-five people were administered this drug and
18 others took inactive placebo; 16 of 25 treated patients and
11 of 18 placebo patients continued the regimen for 12 months.
There was a reduced incidence of relapses in the pirfenidone
group (12.5%) compared with the placebo group (45.5%). Those
taking pirfenidone had significantly higher scores on a scale
rating neurological function, as well as improved bladder function.
Further study of the drug is warranted to determine its safety
and effectiveness in MS.
Conserving Energy to Battle Fatigue
(Poster presentation)
Dr. Virgil Mathiowetz and colleagues (University
of Minnesota, Minn.) evaluated a six-week energy conservation
course as a strategy for combating fatigue, with funding from
the National MS Society. This course, taught by an occupational
therapist, involves effort-saving devices, eliminating or delegating
tiring tasks, and including rest periods into every day. A total
of 169 people with MS were randomly assigned to the course or
a control group. Using scales to measure the impact of the course,
the investigators found significant improvements in fatigue,
self-efficacy, and some aspects of quality of life in those
who took the course. This study is helping to identify simple
energy-saving strategies to enable people with MS to manage
fatigue.
A Clue to MS Progression? (Poster
presentation)
Dr. William T. Regenold (University of Maryland
School of Medicine, Baltimore) and colleagues investigated whether
the appearance of glucose, a sugar, in cerebrospinal fluid (CSF)
is associated with MS progression. With funding from the Pilot
Research Award Program of the National MS Society, they measured
the concentration of several molecules in CSF samples from 50
people with relapsing-remitting MS, 50 people with secondary-progressive
MS, and 12 people without MS. People with both types of MS had
significantly higher levels of sorbitol and lactate than controls
without MS, and people with secondary-progressive MS had significantly
higher levels of glucose and lactate than those with relapsing-remitting
disease. These results indicate that there may be differences
in glucose metabolism in MS, and differences between people
with different types of disease as well, but further study is
warranted to determine an association between the findings and
the cause of MS progression.
(With information from the National MS Society
[USA])
Disclaimer
The Multiple Sclerosis Society of Canada is an independent,
voluntary health agency and does not approve, endorse or recommend
any specific product or therapy but provides information to
assist individuals in making their own decisions.
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