More than 10,000 researchers and practicing
neurologists from around the world gathered
at the 60th Annual Meeting of the American
Academy of Neurology in Chicago from April
12-19. A record 338 presentations were related
to multiple sclerosis. National MS Society
grantees were among those presenting novel
findings on many different aspects of MS research.
Details
John Dystel Prize Presentation
Professor Stephen L. Hauser, MD, received the
National MS Society/American Academy of Neurology’s
2008 John Dystel Prize for Multiple Sclerosis
Research, for his pioneering studies on genetic
susceptibility to MS, and for his role in translating
findings on the role of immune B cells in MS
into clinical trials.
Dr. Hauser (University of California at San
Francisco) spoke strongly about the roadblocks
that exist in MS research, in particular, to
translating basic findings to new therapies. “The
greatest threat to our progress in understanding
MS is the fact that the pipeline of outstanding
young clinician scientists is falling.” This
is a growing area of concern and may be due
in part to fewer opportunities for research
funding from NIH and higher financial pressures
from increasing costs of college and medical
school.
He also spoke of the great potential for genetics
research. “By 2013 we will know all common
variants [genetic variations] that influence
MS,” he said. “We will also know
why some populations are resistant to MS.” This
and other progress in understanding MS genes
should help us identify the cause of this disease
and pinpoint new therapeutic targets.
Dr. Hauser spoke about the meaning of this
award, “This Prize reminds us of the
ultimate goal of our research efforts: to help
people with MS
Promising Results from MS Clinical Trials
Many presentations focused on new data analyzed
from ongoing or completed clinical trials in
multiple sclerosis. Following are a few examples
of the exciting work being done by investigators
and pharmaceutical and biotechnology companies
around the world.
Experimental Agents under Study
A previously reported six-month,
phase 2 controlled study of oral fingolimod (FTY720, Novartis
Pharma AG) showed possible benefits in
relapse rate and MRI-detected disease activity
in relapsing
MS, and the drug is now being tested in
a larger, phase 3 trial. Results showed that
73% of patients
who began the study on FTY720 5 mg remained
free from relapses after three years, and
68% of those who began the study on FTY720
1.25
mg remained relapse-free. Results also
showed an average annualized relapse rate
of 0.20
(meaning one relapse in five years) and
89% were free of active brain lesions on MRI
(vs.
84% at two years)
Dr. Hideki Garren (Bayhill Therapeutics)
and colleagues reported additional data
from a
phase II study of BHT-3009 (one of two
doses (.5 mg or 1.5 mg) vs. inactive placebo)
in
289 people with relapsing-remitting MS.
While the study did not show a statistically
significant
difference in active MRI lesions between
those on therapy and those on placebo, Dr.
Garren’s
presentation focused on findings from 80
patients from whom cerebral spinal fluid
(CSF) was collected
before beginning therapy to profile those
patients who responded to the drug based
on initial
CSF levels of immunoglobulin (IgG). In
patients whose IgG levels were greater than
or equal
to 2.5 mg/dl at baseline, the primary goal
of the study was achieved, that is, active
lesions observed on MRI scans were reduced
from weeks 28 to 48 by 44% versus placebo.
Annualized relapse rates for this group
were reduced by 36%. Dr. Garren stated that
a
new trial is in planning stages.
Dr. Anjali Shah (University of Texas
Southwestern Medical Center, Dallas) and colleagues
reported
on a study of botulinum toxin type
A injections
in 19 people with MS and spastic foot drop.
These injections have been shown in clinical
trials to relieve spasticity in individual
muscles for up to three months, without
any significant side effects. In the current
study,
botulinum toxin type A was injected into
leg muscles, and patients underwent 6-8 weeks
of
physical therapy. A significant improvement
in spasticity and emotional quality of
life occurred, and MS disease activity remained
stable.
Dr. Michael Kaufman (Carolinas Medical
Center, Charlotte) and colleagues reported
final results
of the phase II “CHOICE” study
of daclizumab (PDL Biopharma and Biogen Idec)
in 230 people with relapsing forms of MS
who were taking interferon beta. Participants
received
either interferon + placebo or interferon
+ Daclizumab. At 24 weeks, benefit was seen
in
both treatment groups with a larger magnitude
of effect in the higher dose treatment arm.
Preliminary safety data showed a similar
overall infection rate across all treatment
groups.
Two groups reported on the use of
low dose naltrexone (LDN). Dr. Gianvito Martino
(San
Raffaele Hospital, Milan, Italy) and colleagues
administered 5 mg of LDN to 40 people with
primary-progressive MS for 6 months, evaluating
its safety and effects on spasticity, pain
and fatigue. Five patients dropped out.
Significant improvements were shown in fatigue
and depression.
Transient increases in liver enzymes, urinary
tract infections, mild agitation and sleep
disturbance were the most common adverse
events.
Dr. Bruce Cree (University of California,
San Francisco) and colleagues reported that
eight
weeks of treatment with LDN significantly
improved quality of life (specifically, mental
health,
pain, and self-reported cognitive function)
in 60 people with MS as measured by the
MS Quality of Life Inventory. No impact was
observed
on physical quality of life (such as fatigue,
bowel and bladder control, sexual satisfaction,
and visual function). Vivid dreaming was
reported during the first week of treatment
by some
patients, but no other adverse effects
were reported.
Dr. Alasdair J. Coles (Adenbrooke’s Hospital,
University of Cambridge, UK) reported 24-month
results from a phase 2 clinical trial comparing
high and low doses of the immune-suppressing
monoclonal antibody alemtuzumab (Genzyme Corporation)
with Rebif® (interferon beta-1a, EMD
Serono, Inc. and Pfizer, Inc.) in people
with relapsing-remitting
MS who had never taken any other disease-modifying
therapies. Pooled data on those taking either
dose of Campath indicate a 73% reduction
in the risk of MS relapse compared with those
on Rebif and a 71% reduction in the risk
for
sustained accumulation of disability. Immune
thrombocytopenic purpura, thyroid adverse
events, and infections occurred more frequently
in
the alemtuzumab groups.
In a special plenary session, Professor
Moses Rodriguez (Mayo Clinic) described
the painstaking
steps his team has taken to develop a new
therapy for MS and possibly other disorders
using naturally
occurring antibodies, produced by the body’s
immune system. Much of his ongoing research
has been funded in part by the National
MS Society. In animal models of MS, the
team
has found antibodies that stimulate the
repair of the insulating myelin coating
on nerve
fibers.
Myelin damage is a hallmark of MS, and
its repair may improve function and protect
the
underlying nerve fibers. Dr. Rodriguez
stated that the antibodies will soon be
studied
in human clinical trials.
Studies of Approved MS Drugs
In a small study of 12 people taking Tysabri® (natalizumab,
Biogen Idec, Inc and Elan Pharmaceuticals),
Dr. B. Khatri (Aurora St. Luke’s Medical
Center, Milwaukee) and colleagues explored
whether plasma exchange (a blood-cleansing
process that involves removing and replacing
the liquid portion of blood) could reduce
the concentration of Tysabri in the blood
and possibly
serve as an intervention in case a patient
develops PML, (progressive multifocal leukoencephalopathy)
-- a brain disease that occurred in three
people (two of whom died) who had been in
clinical
trials of Tysabri. Tysabri concentration
was decreased by 90% or more compared with
levels
before plasma exchange. Plasma exchange was
well tolerated, with no increase in MS disease
activity. All patients returned to Tysabri
treatment without complications. Further
study is needed to determine whether plasma
exchange
is an effective intervention for PML.
The
latest safety data on Tysabri, also presented,
revealed that as of late March,
26,000 patients
are now on Tysabri worldwide, and 9,900
have been exposed to drug for at least 1 year,
and
3,600 exposed for at least 18 months. No
new cases of PML have occurred.
Copaxone (glatiramer acetate, Teva
Pharmaceutical Industries Ltd.) significantly
reduced the
risk of developing MS and delayed the development
of MS in individuals with CIS (clinically
isolated syndrome, a first event suggestive
of MS) enrolled
in the PreCISe study. In the Copaxone group,
the risk of developing clinically definite
MS was reduced by 45% versus placebo, and
the time to development of definite MS was
delayed
by 386 days more than in the placebo group.
The proportion of patients who developed
MS was 43% in the placebo group versus 25%
in
the Copaxone group.
Dr. Paul O’Connor (University of
Toronto) and colleagues reported results
of the BEYOND
study, evaluating the effectiveness of
high and low doses (500 mcg vs. 250 mcg)
of Betaseron
(interferon beta-1b) and Copaxone. No differences
were found in the risk of relapse, the
primary endpoint, or secondary endpoints
such as
MRI findings. The findings indicate that
the currently
approved dose of 250 mcg of Betaseron is
the optimal dose.
Dr. Emmanuelle Le Page (Hôpital Pontchaillou,
Rennes, France) and colleagues administered
Betaseron following treatment with mitoxantrone
and methylprednisolone or methylprednisolone
alone to 109 people with very active relapsing-remitting
MS, hoping to increase the effectiveness
of Betaseron with a short course of immunosuppressive
treatment. Worsening disease activity as
measured
by the EDSS (a scale used to measure disease
activity) was delayed significantly longer
in the mitoxantrone/methylprednisolone
group, and the percentage of patients whose
EDSS
score worsened by at least 1 point was
reduced by
65% in this group compared with the methylprednisolone
group. The annualized relapse rate was
reduced by 61.5% in the mitoxantrone/methylprednisolone
group, and the percentage of relapse free
patients was 53% in versus 26% in the methylprednisolone
group. No serious adverse events occurred
during
follow-up.
Dr. Bianca Weinstock-Guttman (State
University of New York, Buffalo) and colleagues
evaluated
the patterns of genes that are expressed
(i.e., genes that are turned on or off) in
response
to treatment with interferon beta. They
reported that people with MS who have good
clinical
responses to treatment demonstrate a different
pattern of gene expression responses compared
with those who experienced only a partial
therapeutic effect. A different profile of
gene expression
was also seen in patients who experienced
persistent side effects to treatment. These
results raise
the possibility that doctors may eventually
be able to determine early in the course
of treatment whether a person will respond
to
therapy and make appropriate medication
adjustments.
Research on Tracking and Understanding MS
Aside from the range of clinical studies, the
AAN also featured cutting-edge findings from
genetics, laboratory and imaging studies.
These efforts are crucial to understanding
and tracking MS.
New results were reported by Dr.
Philip De Jager and colleagues in The
International Multiple
Sclerosis Genetics Consortium (IMSGC),
a group of international MS genetic experts
created
with funding from the National MS Society,
who previously completed the largest replicated
whole genome scan (scan of all the genes
in the body) for MS to date, identifying two
new
genetic variations associated with MS.
Adding 954 people with MS and 581 controls
without
MS to their previous study, they identified
several new genetic variations associated
with MS, including two genes that instruct
how cells
bind to each other (P Cadherin 7 and CTNNA3).
Two previously identified variations were
confirmed, including CD58, which instructs
another cell
adhesion molecule. The team is seeking
to further validate findings on 5000 genetic
variations
with information from 1,500 people with
MS and 1,500 controls without MS.
In other genetics news, Dr. Bruce Cree
and colleagues reported on genetics studies
in
African Americans. Focusing on ethnic groups
with lower susceptibility to MS (such as
African-Americans) and higher susceptibility
(such as individuals
of Northern European descent), and searching
for commonalities and differences may help
pinpoint chromosome regions that contain
MS genes. Comparing 770 African Americans
with
MS and 813 whites with MS, this team identified
an association in the AA population with
variations in the gene that instructs the
RAGE protein – different
variations than had previously been identified
in whites. RAGE has important immune and
nervous system functions.
For the first year ever, there
was an entire poster session on optical
coherence
tomography (OCT), a relatively new technique that
measures the thickness of the nerve layer
at the back
of the eye (retinal nerve fiber layer),
and can detect thinning of that layer as
a possible
means of tracking MS progression. Medical
student Esther Bisker (University of Pennsylvania,
Philadelphia) and colleagues presented
results
on using OCT to measure the optic disc
(the head of the optic nerve) as well as
retinal nerve fiber layer in 233 people
with MS
and
96 people without MS. The measurements
were significantly different, and the group
concluded
that using OCT for optic disc measurements
as well as retinal nerve fiber layer
may help to identify eyes most at risk for
nerve
fiber
loss. Further testing of OCT should map
out its potential usefulness as a tool for
tracking
disease progression and as a much-needed
outcome measure for clinical trials aiming
to protect
or repair the nervous system.
Dr. Francesca Bagnato (NINDS, Bethesda,
MD) and colleagues tested the safety and
tolerability
of a very strong 7 tesla magnet in MRI scans
of 10 people with MS and 10 controls without
MS. (Standard MRIs use a 1.5 tesla magnet.)
So far, seven in each group have been studied
and have tolerated the scan well. Transient
dizziness was reported by two people with
MS during table motion. The more powerful
magnet
allowed investigators to better visualize
lesions (areas of tissue damage or disease
activity),
for example, differentiating between lesions
with or without iron accumulation, and differentiating “substructures” within
lesions, which may indicate multiple breakdowns
of the blood-brain barrier. The greater contrast
presents a useful tool for characterizing
tissue damage in MS.
Dr. Shanu Roemer and colleagues from the
MS Lesion Project examined brain tissue
obtained
via biopsy from people with early
MS for
signs of inflammation in the cortex and
meninges – outer
membranes lining the brain. Cortical inflammation
was observed in 39% of patients, and 15
of 18 available samples of meninges. This
study
follows up on previous findings from ECTRIMS
2007, in which investigators from London
and Rome reported on damage in these areas
in people
with secondary-progressive MS.
Fatigue can be a severe problem for people
with MS but little is known about its cause.
Dr. Robert Bermel (Cleveland Clinic Foundation)
and colleagues utilized a technology called “functional
MRI” to evaluate the level of activation
of various parts of the brain during a motor
task. They found that higher levels of MS
fatigue correlated with a lower level of
activation
of a brain region called the thalamus. This
begins to help scientists better understand
the problem of fatigue in MS and may eventually
lead to improved ability to treat MS-related
fatigue.
These and many other presentations reflect
the rapid pace of MS research today.
Avonex is a registered trademark of Biogen
Idec
Betaseron is a registered trademark of Bayer
HealthCare Pharmaceuticals
Botox is a registered trademark of Allergan,
Inc.
Copaxone is a registered trademark of Teva
Pharmaceutical Industries Ltd
Rebif is a registered trademark of EMD Serono,
Inc.
Tysabri is a registered trademark of Biogen
Idec and Elan
[With information from the National MS Society (USA)]
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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.
