More than 10,000 researchers and practicing
neurologists from around the world gathered
at the 59th Annual Meeting of the American
Academy of Neurology in Boston from April 28
to May 4. Well over 200 presentations were
about multiple sclerosis. National MS Society
grantees were among those presenting novel
findings on many different aspects of MS research.
(For free access to the abstracts of presentations
given at this year’s meeting, go to:
www.abstracts2view.com/aan2007boston)
Here are a few highlights:
John Dystel Prize Presentation
“I do not think it is too bold to think
about curing MS,” stated Dr. Howard Weiner – winner
of the 2007 John Dystel Prize for MS Research awarded by the National MS Society (U.S.A.)
and AAN – during a presentation in which
he talked about how far MS research had come
since he started treating people with MS in
1972. “Enormous progress has been made.”
Dr. Weiner, of Harvard’s Brigham and
Women’s Hospital, spoke of a multifaceted
cure that would address the diverse, chronic
nature of multiple sclerosis: administering
immunotherapy early, to halt disease progression;
employing stem cells to reverse neurological
damage; and finding MS biomarkers – predictive
hallmarks – with an end goal of developing
methods of prevention.
Dr. Weiner also reported on the scope of research
conducted at the Partners MS Center that he
founded at Brigham & Women’s Hospital,
including the Comprehensive Longitudinal Investigation
of MS at Brigham (CLIMB). This study involves
following 1000 people with MS (760 have been
enrolled as of this writing) from disease onset
using yearly imaging, clinical, immunologic,
cognitive and quality of life measures.
At this year’s AAN meeting, Dr. Weiner’s
team – including Dr. Rohit Bakshi – reported
on the use of the Magnetic Resonance Disease
Severity Scale (MRDSS), a method of tracking
MS disease activity that combines assessments
of tissue damage with tissue volume loss. The
group used the MRDSS to track 103 people over
three years, and found this scale to more closely
predict disease progression than MRI or clinical
measures. (Abstract #P02.042)
Previous Canadian Dystel prize winners have
included the late Dr. Don Paty, University
of British Columbia and more recently, Dr.
Jack Antel of The Montreal Neurological Institute.
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 oral therapies:
Dr. Giancarlo Comi (Scientific
Institute and University Ospedale San Raffaele,
Milan) and
others administered 0.3 mg or 0.6 mg
doses of oral laquinimod (Teva Pharmaceutical
Industries,
Ltd., Active Biotech AB) daily for 36
weeks to 306 people with RR MS. The primary
goal
was to determine if the immune-modulating
drug would reduce the number of active MRI
brain
lesions. In those taking 0.6 mg, active
lesions decreased significantly, by 38%,
compared with
the placebo group, but not in those on
the lower dose. Participants tolerated both
doses,
experiencing transient increases in liver
enzymes.
According to a press release from
the companies, the majority of people who
participated
in the study continued treatment in an ongoing,
blinded, 9-month extension study, to be
followed
by an open-label study in which patients
will receive .6 mg for an additional 24 months
(Abstract
#S02.002)
Dr. Claudia Kaiser (University of
Illinois, Chicago) and colleagues studied
whether oral pioglitazone (Actos®, Takeda
Pharmaceuticals) – a
drug approved for diabetes that has anti-inflammatory
effects – was safe to use in people
with MS already taking Avonex® (interferon
beta-1a, Biogen Idec, Inc.). Secondary goals
of the
study were to determine the effect on disease
activity and brain tissue loss as observed
using advanced imaging technology.
In a small
study, pioglitazone (30 mg/day) or placebo
was administered for one year
to 22 people with RR MS. The drug was well
tolerated.
There was no increase in clinical measures
of disease activity, and disease activity
observed on imaging scans decreased significantly
in
the pioglitazone group, as did brain tissue
volume loss. The authors note that further
study of this drug is warranted by these
findings. (Abstract #S02.006)
Dr. Andrew Goodman (University
of Rochester) presented detailed results
of a
phase 3, placebo-controlled study of oral
Fampridine-SR (sustained-release formula
of 4-aminopyridine,
Acorda Therapeutics) in 301 individuals
with all types of MS. Fampridine blocks tiny
pores,
or potassium channels, on the surface of
nerve fibers. This blocking ability may improve
the
conduction of nerve signals in nerve fibers
whose insulating myelin coating has been
damaged by MS.
Thirty-five percent of those
on active therapy experienced an average
of 20% improvement
in
walking speed (in the timed 25-foot walk),
which was maintained over the 14 weeks of
therapy. Improvement was also noted in the “MS
Walking Scale 12,” a measure designed
to assess how meaningful the improvement
was. Other positive outcomes included increased
leg strength in those on active treatment.
Two serious adverse events that led to the
discontinuation of dosing were anxiety in
one
participant and a seizure during a serious
infection in another. (Abstract #S32.003)
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. During
the phase 2 study, investigators also measured
depression at the beginning of the study
and
also at 3 months and 6 months into the
trial in 239 participants.
Dr. Ludwig Kappos
(University Hospital, Basel, Switzerland)
and colleagues reported
that those
on either of two doses of fingolimod showed
significant improvement in their depression
scores versus those on inactive placebo.
After the study, all participants were invited
to
continue or begin taking the active therapy.
During 18 months of this extension study,
the improvement in depression scores was
sustained
and extended to those who had switched
from placebo to fingolimod. (Abstract #P06.085)
Combination Therapies:
Investigators continued
to report data from a 15-month study exploring
the effectiveness
of a brief (3 monthly infusions), low
dose of mitoxantrone (such as Novantrone®,
EMD Serono) followed by initiating therapy
with
Copaxone® (glatiramer acetate, Teva
Neuroscience) in 40 patients with relapsing-remitting
MS.
This regimen has been previously reported
as safe and well-tolerated, and to have
reduced
active MRI-detected lesions by 70% after
15 months compared to those taking Copaxone
alone.
Dr. Douglas L. Arnold (Montreal
Neurological Institute) and colleagues
presented the effects
of the combination therapy on specific
MRI (magnetic resonance imaging) measures,
and
found significant additional benefits for
those on combination therapy, including
reductions in active MRI lesions and
volume of lesions,
and reduction of the proportion of active
lesions
that evolved into chronic “black holes” indicative
of chronic tissue damage. (Abstract #P06.104)
In
related work, Dr. Timothy Vollmer (Barrow
Neurological Institute, Phoenix) and
colleagues reported on MRI outcomes in
an extension
of the study after an additional 9 months
of Copaxone
in 30 patients who participated. The
investigators found that MRI-detected benefits
were achieved
early on and were sustained through the
24-months compared to MRI scans before
treatment. (Abstract
#06.096)
Dr. Luanne Metz (University of Calgary,
Alberta) and colleagues studied the effects
of adding on oral minocycline – an
antibiotic – to
Copaxone versus treatment with Copaxone
and placebo in 40 people with RR MS. Minocycline
has been shown to inhibit proteins that
contribute
to the immune attack in MS. The primary
outcome measured was a reduction in active
brain
lesions. This small pilot study was not
designed to
show statistical significance, but did
show a trend to improvement in this outcome,
as
well as in relapse risk. . Treatment was
safe and well tolerated. The authors note
that further
study of minocycline is warranted because
it is safe and inexpensive. (Abstract #S02.003)
Dr.
Jeffrey Cohen (Cleveland Clinic Foundation)
and colleagues presented results
from the Avonex Combination Trial – the
ACT study – in which the drug was
combined with oral methotrexate, intravenous
methylpredisolone
or both in people with RR MS who were experiencing
disease activity while taking Avonex. Results
so far suggest trends that favor the combination
of all three, but no differences have reached
statistical significance. Further data
analysis is ongoing. (Abstract #S02.005)
Experimental infusions:
Two groups reported on studies of rituximab
(Rituxan®, Genentech and Biogen
Idec), a drug that depletes immune
B cells, which
may play a role in the immune attack
on brain and spinal cord tissues
in MS. Dr.
Amit Bar-Or
(Montreal Neurological Institute)
and collaborators administered two
intravenous infusions
of rituximab two weeks apart, and
then another dose six
months later, to 26 people with relapsing-remitting
MS (RR MS, a course of MS characterized
by clearly defined flare-ups followed
by partial
or complete recovery periods). Patients
were followed for one year.
The primary
goal of the study was to determine
the safety and tolerability of the
drug, and secondary goals were to
assess its effects
on relapse rate and disease activity
observed on MRI scans. Adverse events
consisted
of mild
to moderate infusion-related reactions.
The number of active (gadolinium-enhancing)
MRI-detected
brain lesions was significantly reduced
from week 4 through week 48. Relapses
were also
reduced significantly. (Abstract #S02.001)
Dr.
Stephen Hauser (University of California
at San Francisco) and colleagues administered
two infusions of rituximab two weeks
apart
to 69 people with RR MS and inactive
placebo to 35 people. The primary goal of
the study
was to determine the drug’s effect
on active brain lesions, and other
goals included
the proportion of patients relapsing
by week 24. The number of active lesions
was
reduced
by almost 90% in the group taking rituximab
versus those on placebo, and significantly
fewer people in the treatment group
had relapses. More infusion-related
reactions
occurred in
the group taking rituximab. (Abstract #S12.003)
Rituximab
is approved for use with certain types
of lymphoma and a form of arthritis.
The drug has been associated with severe
adverse effects including fatal infusion
reactions
and progressive multifocal leukoencephalopathy;
these have not occurred in the MS studies.
A clinical trial of rituximab is ongoing
in 435 people with primary-progressive
MS
(a course
of MS characterized by a slow but nearly
continuous worsening of disease from
the onset).
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 Campath® (alemtuzumab,
Genzyme) 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.
Those taking either dose of Campath experienced
significant reductions in the risk
of MS relapse compared with those on
Rebif (at
least 75%
reduction) and at least 65% reductions
in the risk for progression of disability
over 2 years,
compared with Rebif. Serious adverse
events have led the company to suspend
this study,
however: there were a significantly
greater proportion of patients with thyroid
problems
after two years of Campath treatment,
and six persons on either dose of Campath
developed
severe idiopathic thrombocytopenic
purpura (ITP, a condition in which low
blood platelet
counts can lead to abnormal bleeding).
One
patient died, and five were treated
and now have normal platelet counts.
Participants
continue
to be monitored for ITP. According
to a Genzyme press release, the company
is in
active discussions
with regulatory authorities regarding
the Campath program, and is planning
two larger-scale
phase
3 clinical trials. (Abstract #S12.004)
Followup studies of approved therapies:
Dr.
Mark Freedman (University of Ottawa,
Ontario, Canada) and colleagues reported
on a follow-up
to the BENEFIT study, in which treatment
with Betaseron® (interferon beta-1b,
Bayer HealthCare Pharmaceuticals) was
shown to delay the onset
of clinically definite MS in people
at high-risk for the disease compared
with
people who did
not receive treatment. In the follow-up
study, both groups are now receiving
Betaseron, and
the study is assessing the impact of
early treatment versus delayed treatment
on the progression
of MS. Of the original study group
of 468 people, 418 are enrolled in the
follow-up
study, with
261 in the early treatment group, and
157 in the delayed treatment group. The
results after
one year show that early treatment
with Betaseron reduced the risk for disease
progression – as
determined by the EDSS scale of disease
activity – by
40%. The study is continuing for two
more years. (Abstract #S02.004)
A new formulation
of Rebif® (interferon
beta-1a, EMD Serono, Inc. and Pfizer,
Inc.) is proving to be more tolerable than
the
original formulation, according to
data from an ongoing
two-year study presented by Dr. James
Simsarian (Neurology Center of Fairfax)
and colleagues.
The new formulation is designed to
reduce the development of neutralizing
antibodies
(Nabs),
which are immune system proteins that
may reduce effectiveness of interferon
treatments.
In
this study, 260 people with relapsing
forms of MS took 44 mcg of reformulated
Rebif three
times weekly, and the results were
compared with historical data from the
EVIDENCE study
(in which the original Rebif was compared
to Avonex.
At 48 weeks, 13.9% of patients
treated with the new formulation were
Nab positive,
compared
with 24.4% of patients in the EVIDENCE
study at 48 weeks. The proportion of
patients who
spontaneously reverted to being Nab
negative was double that from the EVIDENCE
study,
and the concentration, or titers, of
Nabs were
generally lower, with half as many
showing titers over 1000 NU/mL. Injection-site
reactions were lower compared to the
EVIDENCE
study,
and the investigators found no unexpected
safety issues or adverse events. (Abstract
#P06.077)
Among reports related to Tysabri® (natalizumab,
Biogen Idec and Elan Pharmaceuticals),
Dr. C. Bozic and colleagues (Biogen Idec,
Inc.,
Cambridge, MA) reported on its safety
for relapsing MS. No additional patients
are known to have
developed PML (progressive multifocal
leukoencephalopathy, a rare and frequently
fatal disease of the
central nervous system) in some 18,000
people worldwide who have been exposed to
Tysabri
at some point during or after clinical
trials. (During clinical trials, two patients
with
MS who were taking Tysabri in combination
with interferon beta-1a developed PML; one
of those
cases was fatal. A third case of PML,
also fatal, was uncovered in another person
who
had taken Tysabri during a clinical
trial for Crohn’s disease.)
Thus far
over 5,700 patients have received infusions
of Tysabri in the U.S. through
the mandatory TOUCH™ prescribing
program. These patients have received
an average
of 3.4 infusions (ranging from 1 to
8). The overall
reporting rate of serious hypersensitivity
reactions (allergic reactions) to
infusions has been 0.8%; the majority
occurred at
the second infusion. Most of those
experiencing serious hypersensitivity
to infusion, including
anaphylaxis (a severe, whole-body
allergic reaction), had received treatment
before
market
suspension, and experienced anaphylactic
reactions after being re-dosed after
an extended period
without treatment. (Abstract #P06.0895)
Results
of an open-label extension study of
the two-year AFFIRM clinical trial
that
compared
Tysabri against inactive placebo were
presented by Dr. Paul W. O’Connor (St. Michael’s
Hospital, Toronto) and colleagues. The data
suggest that the drug’s benefits
continued beyond two years. In the
original study,
627 patients with relapsing MS were
on active treatment,
against 315 patients on placebo. Significant
benefit was seen in both relapse rates
and progression of disability.
In the extension
study, 531 patients continued on Tysabri
and 259 of those on placebo
were switched to Tysabri; the plan
was for both
groups to be followed for an additional
2 years. Before the extension study
was stopped early
because of the above-mentioned incidents
of PML, many of the participants had
received additional doses of Tysabri.
The median
duration
of Tysabri treatment experienced
by those originally in the AFFIRM treatment
group
was 2.72 years,
and for AFFIRM placebo patients 0.60 years.
Evaluating data available from the extension
study, the investigators reported
that Tysabri continued to decrease the risk
of
disability
progression at 3 years, with the
cumulative probability of disability progression
in
those continuing on therapy at 13%,
compared to 23%
in placebo patients at the end of
the 2-year AFFIRM study. The rate of relapse
also
decreased in those switched from placebo
and continued
to decrease in those continuing on
therapy. (Abstract #P06.082)
Other Important Studies
Do sleep disturbances contribute to fatigue?
Fatigue
is a frequent and troubling symptom of
MS. Dr. Mark Gudesblatt
and colleagues (South
Shore Neurologic Associates,
Bay Shore, NY) investigated the frequency
of sleep disorders
in 27 individuals with relapsing-remitting
and secondary-progressive
MS. Using “polysomnography,” a
technique that measures brain
activity, airflow and other phenomena during
sleep,
the investigators
found that all of the patients
had sleep abnormalities that could contribute
to
fatigue. These abnormalities
included obstructive sleep
apnea, delayed REM onset and impaired sleep
efficiency.
The investigators
concluded that patients complaining
of fatigue in MS should have sleep studies
done to evaluate
the possibility that unrecognized
sleep
disorders that might be responsive
to non-medication therapy. This study adds
to a growing body
of literature related to
sleep disturbances in MS. (Abstract #P04.083)
Looking for ways to predict MS:
Finding a way to predict whether a person
with a single neurological
episode will go on
to develop MS would open up
the possibility for earlier, possibly preventive,
treatment.
Dr. Jeffrey L. Bennett (University
of Colorado
Health Science Center) and
colleagues have been searching for a way
to predict
whether
a person with an early possible
symptom of MS (a condition called CIS)
will go on to develop
definite MS. Comparing blood
and spinal fluid from people with definite
MS versus those with
CIS, the team found that the
presence
of immune antibodies with a particular
molecular component
(called heavy chain variable
domain VH4/VH2) could reliably predict
that an
individual
with CIS would develop definite MS within 6 months.
Further research is needed
to firm up this potentially important finding
as
a reliable
biomarker that can facilitate
early diagnosis. (Abstract #S26.004)
Dr.
Leonora Fisniku and the well established
MS investigation group at the
Institute of
Neurology (Queen Square, London)
presented results of 20 years of follow-up
of 85
patients who originally presented
with CIS suggestive
of MS and who had MRI scans
at the outset. After 20 years, 63% developed
definite
MS. Those who showed abnormal
signs
on their original
MRI were more likely to develop
MS (50 out of 57 individuals), and those
whose original
MRI scans were normal were
less likely to develop
definite MS (5 out of 28).
The investigators also found that those who
still
had a relapsing-remitting
course after 20 years had lower
brain lesion volumes than those whose disease
evolved
into secondary-progressive MS.
(Abstract #S42.004)
Tools to Measure Disease Activity:
Drs.
Bianca Weinstock-Guttmann, Murali Ramanathan
(State University
of New York at Buffalo) and colleagues
tracked
immune changes in the blood
of 52 people with
MS, and used MRI and neurological tests
to monitor
the disease state clinically.
The team reports
that BDNF (brain derived neurotrophic factor),
a protein produced in the brain and
immune cells, increased
in response to disease activity and seemed
to play a protective role.
This study shows
that
BDNF may help to mediate “crosstalk” between
the attacking immune
system and the nervous system in MS, and
may thus be useful in
developing neuroprotective
strategies. (Abstract #P01.057)
The eyes
may be the “windows
to the soul,” but recent research also
suggests they may be a window to monitoring
MS disease activity. Several investigative
teams, including the National MS Society’s
(U.S.A.) Nervous System Repair
team led by Dr. Peter Calabresi
(Johns Hopkins University,
Baltimore) reported on the use
of a new technique called OCT
(optical coherence tomography),
which measures the thickness
of the nerve
layer at the back of the eye
and may prove to be
a simple tool to detect disease progression.
In one study presented by Dr.
Eliza Gordon-Lipkin, the team
found that the thinning of the
nerve layer (retina) at the back
of the eye
echoes
evidence of brain shrinkage
or atrophy, measured by MRI scans
in MS. They conclude
that OCT
may therefore provide global
information regarding disease
progression in the brains
of MS patients.
(Abstract #P02.044)
In another study presented
by Dr. Mathew Pulicken, the team examined
visual function
and the thickness
of the retina in people with
MS and people without MS. They found that
all those with
MS had thinner nerve layers
than those without the disease. They also
found that
people with
relapsing-remitting MS had
comparatively thicker layers than those with
primary-progressive
MS and secondary-progressive
MS. Taken together
with other studies, the team
concluded that OCT can detect sub-clinical
changes
in retinal
layer, and may be useful as
an outcome measure in clinical trials of
neuroprotective
or neuroreparative
therapies. (Abstract #S52.005)
Dr.
Scott Davis, Craig Crandall (University
of Texas Southwestern Medical
Center, Dallas)
and colleagues studied whether
infrared oculography, a method for measuring
an eye
movement abnormality
(internuclear opthalmoparesis,
INO) that occurs in MS, may help to measure
symptoms
and how
treatments affect them. The
team used infrared oculography to determine
if eye movement
slowed during heating, indicating
fatigue, and improved
after cooling. (Many people
with MS experience a temporary worsening
of symptoms when
the weather is very hot or humid.)
In people
with INO and heat sensitivity, eye movement
abnormalities occurred in response
to whole body heating. These
abnormalities decreased to baseline levels
with whole
body
cooling. No such abnormalities
occurred in people with MS without INO, or
in people
without
MS. This study presents a noninvasive
strategy for determining the success of therapeutic
strategies by measuring their
effects on
INO. (Abstract #P03.037)
Dr. Annika M. Berger,
Dr. Charles Guttmann (Brigham and Women’s
Hospital, Boston) and colleagues
explored whether MRI
imaging of the brainstem (the
lower portion of the brain
adjacent to the spinal cord)
would help to estimate MS damage
to the spinal cord.
Spinal imaging is not performed
as often as brain imaging,
due to extra time and expense.
The team reviewed brain and
spinal imaging scans which had been
administered to 50 people
with MS, and found that brainstem
images did
correlate with those from the
spinal cord. These findings
indicate that brainstem images
may help doctors to estimate
spinal cord damage in people
with MS. (Abstract #P02.045)
Update from a Pediatric MS Center of Excellence:
Drs.
Dorothee Chabas, Emanuelle Waubant and
colleagues reported
on the experiences of the
Pediatric MS
Center of Excellence at the University
of California
at San Francisco. The center
has seen 67 pediatric
patients – younger
than 18 – since
January 2006. Among
41 of these patients
who have been diagnosed
with
MS or CIS (a single,
isolated neurologic
event suggesting
loss of nerve-insulating
myelin),
55% were not white,
which is in contrast
to the university’s
adult MS population,
who are 75% white.
Seventy-eight
percent of the
children
are taking one
of the disease-modifying
drugs that were
approved for
adults with MS.
The authors note
the challenges
in diagnosing
MS
in children,
leading to the
large number
of as-yet-undiagnosed
patients. (Abstract
#P04.064)
Investigating MS genes:
Investigators at
the University of California, San Francisco
have been banking genetic
material from MS families and individuals for
more than a decade. That painstaking work,
funded
by the National MS Society, the NIH and others,
is paying
off and permitting the identification
of genes
that make people susceptible or less susceptible
to MS. Beyond susceptibility, the
UCSF researchers
have also been searching for clues to
genes that might help determine the
course of the disease in any individual.
Dr. Darin T. Okuda presented the UCSF
group’s
study of a gene that helps determine a person’s
immune responses. The group
had previously shown that
people who have a gene on
chromosome
6, called HLA DRB1*1501,
were more likely to have
more MS brain lesions than
those
without
the gene. This study involved
about 480 individuals with
MS, half of whom had the
DRB1*1501 gene.
Testing for disease changes
over one year using a series
of clinical measures called
the MSFC
(MS functional composite),
they found a decline
in the measure of cognitive
function, and no difference
for walking and other measures.
This is the first study to
suggest that patients
carrying this particular
gene may be at greater risk
for cognitive problems over
time. This
early finding is not likely
to cause any changes
in clinical practice. (Abstract #S22.001).
Dr.
Bruce Cree (UCSF) and colleagues presented
results of another gene study
suggesting that this same
gene (DRB1*15) and related ones
may be associated with
an earlier average age at disease onset
in African Americans
and a
typical course of MS
(as opposed to opticospinal MS, for example,
where the disease is restricted
to the optic nerve and
spinal cord and has been found to occur
more
often in African
Americans
than in whites). Ongoing
studies by this group and others involved
in the International
MS
Genetics Consortium should
continue to tease out genetic influences
at play in MS.
(Abstract
#P07.085)
Actos is a registered trademark of Takeda Pharmaceuticals
Avonex is a registered trademark of Biogen
Idec
Betaseron is a registered trademark of Bayer
HealthCare Pharmaceuticals
Campath is a registered trademark of Genzyme
Copaxone is a registered trademark of Teva
Pharmaceutical Industries Ltd
Novantrone is a registered trademark of EMD
Serono, Inc.
Rebif is a registered trademark of EMD Serono,
Inc.
Rituxan is a registered trademark of Genentech
and Biogen Idec
TOUCH is a trademark of Elan Pharmaceuticals,
Inc.
Adapted from information provided courtesy
of the National MS Society (USA)
