Focus on MS Drug Trials,
the Immune Attack and Disease Patholog
Multiple sclerosis research took centre stage
at the 23rd Congress of the European Committee
for Treatment and Research in Multiple Sclerosis
(ECTRIMS), held October 10-14, 2007, in Prague.
Results were presented from numerous clinical
trials, indicating the potential within the
MS pipeline. Key findings also were reported
on the development of disease.
Here is just a sample of these presentations.
The full list of presentations and their summaries
(abstracts) are available online at www.akm.ch/ectrims2007.
(available in English language only)
Notes:
1) Many readers prefer to know the source of
funding especially for clinical trials.
Funding sources for clinical studies were
not consistently disclosed in the meeting program;
they are noted below when available. 2) Definitions
of types of MS are noted on the final page.
Details
Trials of Experimental Therapies in the Pipeline
Dr. H. Garren (Bayhill Therapeutics) and colleagues
reported preliminary 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* (RR) MS. BHT-3009 is
a vaccine containing genetic material that
instructs
cells to produce myelin basic protein (MBP),
a component of myelin, an immune target in
MS. It is given by periodic injections into
the muscle. The primary goal was to determine
differences in the rate of new, active brain
lesions (areas of inflammation or active
damage to nerve fiber insulating myelin)
as shown
on MRI scans. Dr. Garren focused this presentation
on safety data, reporting that BHT-3009 was
well tolerated, and also reported that the
agent altered immune responses to MBP and
several other myelin proteins. Information
about the
drug’s effectiveness is to be presented
in the near future. Sponsored by Bayhill
Therapeutics. (Abstract # 48) According to
a company press
release, preparations are underway to conduct
a larger-scale, phase III trial.
A new formulation of Rebif® (interferon
beta-1a, EMD Serono and Pfizer) proved more
tolerable than the original formulation in
a two-year study reported by Dr. Gavin Giavannoni
and colleagues in a poster presentation (48-week
data) and also in a special satellite meeting
(96-week data). 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 open-label study, 260 people with
relapsing forms of MS‡ injected 44 mcg of Rebif
under the skin three times weekly, and the
results were compared with historical data
from the previously completed EVIDENCE study
(in which the original Rebif was compared to
Avonex® -- interferon beta 1a, Biogen
Idec). At 96 weeks, 17.4% of patients treated
with
the new formulation were Nab positive compared
with 21.4% of patients in the EVIDENCE study
at 48 weeks. Injection site reactions occurred
in much fewer of those on the new formulation:
30.8%, compared with 85.8% in the EVIDENCE
study. Funded by Merck Serono International
S.A. (Abstract #P193) The new formulation
of Rebif was approved for release in Europe,
and
according to company press releases, it has
also applied to the U.S. FDA for approval.
Dr. I. Catz and colleagues (University of
Alberta) reviewed the safety of MBP8298 (BioMS),
a synthetic fragment of myelin basic protein
(MBP, a component of myelin), which reduces
the production of spinal fluid antibodies
that react against MBP. Over 11 years of
its use
as an IV injection in clinical trials,
27 patients have received a total of 492
injections, with
152 adverse events, mostly facial flushing,
burning sensation, and nausea/headache.
Of the 39 cases of facial flushing, 35
occurred
before the manufacturing process was improved
in 2003. Fourteen adverse events were serious,
including one death, but none were attributed
to the medication. MBP8298 is currently
under study in two studies in secondary-progressive*** (SP) MS (510 people in the U.S., and 611
people
in Europe) and one study in 218 people
with RR MS. Funded by BioMS Medical Corp.
(Abstract
# P571) Dr. L. Arfors and colleagues reported
on an interim safety analysis of the European
study, showing no significant safety concerns
and no signs of worsening disease on MRI.
All studies are ongoing and are fully enrolled.
Funded by BioMS Medical Corp. (Abstract
# P573)
Dr. G. Mancardi (University of Genoa) provided
an update on the status of hematopoietic
stem cell transplantation (in
which blood or bone marrow stem cells,
usually the patient’s
own, are used to reconstitute the immune
system in hopes of stopping immune attacks
in MS).
From 1995 to 2007, more than 300 people
have been treated. According to a survey
of patients
in the database of the Europe Blood and
Transplantation Group, 63% of people have
improved or stabilized.
From 1995 to 2000, 8% of patients died,
but mortality has been substantially reduced
since
then. The results were best in rapidly
evolving, severe MS. Among 58 cases in
Italy, 63% of
people with SP MS improved or stabilized,
versus 95% of those with RR MS. Dr. Mancardi
pointed
out that this therapy has not yet been
proven to be clinically effective. (Abstract
#72)
Dr. M. Freedman and the Canadian Bone Marrow
Transplantation Study Group reported on
25 patients enrolled in this study who have
active,
relapsing MS with high risk of disease
progression; 15 have received full treatment
(hematopoietic
stem cell transplantation, described
above). No patient has experienced relapses
or has
any new disease activity on MRI. Mild disease
progression has been observed in four people
with high EDSS scores (indicating greater
disability) upon entering the study. Three
patients with
lower disability at entry showed improvement
in their disability scores after treatment.
One person died due to complications in
administering busulfan, one drug involved
in the protocol,
but the protocol has since been changed
to make administration more tolerable.
This study
is ongoing. Sponsored by the Multiple Sclerosis
Foundation of Canada. (Abstract #73)
Dr. X. Montalban (University of Barcelona)
and colleagues reported on preliminary 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 an interferon beta. In this study,
while continuing on their interferon treatment,
78 people received 1 mg daclizumab injection
under the skin every 4 weeks, 75 received
2 mg every 2 weeks, and 77 received placebo,
for 24 weeks and were observed for 48 weeks
afterward. Ninety percent of people completed
the study and the investigators found the
addition
of daclizumab to interferon beta generally
well tolerated. The primary endpoint of the
study – number of new or enlarged areas
of active damage on MRI – was significantly
reduced by 72% in the high-dose group compared
with placebo. The low-dose group showed a 25%
reduction compared with placebo – not
a statistically significant finding. Funded
by PDL Biopharma. (Abstract #50) A company
press release indicated that they are initiating
a further study by the end of 2007.
Dr. H. Ehrenreich (Max Planck Institute of
Experimental Medicine, Gottingen, Germany)
and colleagues reported results from a
small, uncontrolled study of a laboratory-produced
version of erythropoietin,
a naturally-occurring hormone used to treat
anemia, in 8 patients
with chronic, progressive (secondary-progressive)
MS. The rationale was that erythropoietin
has potential as a nervous system-protecting
agent.
Five people took a high dose of the intravenous
drug, along with two control patients who
had Parkinson’s disease, and three
received a low dose. The group was followed
for 48 weeks.
Although this was primarily a safety study,
with no adverse events reported, the investigators
also reported that motor and cognitive
function improved and improvements persisted
for three
to six months after treatment. The low-dose
and control groups did not improve. Funding
source not published. (Abstract #118)
Dr. J. Drulovic (University of Belgrade)
and colleagues reported on a study of MN-166 (MediciNova),
an experimental oral drug, in 292 people
with RR MS (93%) or SP MS (7%). People were
randomly
assigned to receive MN-166 at low or high
dose (30 or 60 mg) or placebo. There was no
significant
difference seen between the groups in the
study’s
primary endpoint -- the accumulation of disease
activity observed on MRI. However, MN-166 was
associated with a significant reduction in
loss of brain tissue volume over one year,
and also with a significant increase in time
to first relapse. Gastrointestinal events – mostly
mild – occurred in 22% of the high-dose
group, 15% of the low-dose group, and in
8% of those on placebo. Additional early
studies,
including studies investigating higher doses,
are planned. Funded by MediciNova Inc. (Abstract
#52)
Studies of Approved Therapies
In a head-to-head comparison trial, Dr. D.
Mikol and researchers from the REGARD
Study Group compared Rebif ® 44mcg (interferon
beta-1a, EMD Serono and Pfizer) against Copaxone® 20
mg(glatiramer acetate, Teva Pharmaceutical
Industries) in RR MS. In this study, 386 participants
were randomly assigned to receive the current
formula of Rebif 44 mcg 3 times per week and
378 received Copaxone20 mg per day for 96
weeks. The primary goal was to determine whether
there was a difference in the average time
it took for a first relapse (attack) to occur
in patients on the two drugs. No statistically
significant differences were seen.
Overall the investigators noted that the
study population had much less active disease
compared to previous trials in relapsing-remitting
MS, and suggested that this might make it
difficult to draw reliable conclusions from
this data.
In a special satellite meeting and in a poster
presentation, Dr. M. Panzara (Biogen
Idec) and colleagues presented updates on
its
TOUCH™ prescribing
program in the U.S. and TYGRIS global
observation program for Tysabri® (natalizumab,
Biogen Idec and Elan Pharmaceuticals),
a treatment
approved for relapsing forms of MS given
by IV infusion every four weeks. The TOUCH
program
is designed to track opportunistic infections
and to understand their risk factors. As
of September 2007, approximately 17,000
people
are currently being prescribed Tysabri
or are involved in clinical trials, 10,500
of those
in the U.S. No new cases have been confirmed
of PML (progressive multifocal leukoencephalopathy),
a brain disease that occurred in three
people (two of whom died) who had been
in earlier
clinical trials of Tysabri. Funded by Biogen
Idec, Inc and Elan Pharmaceuticals. All
told, about 26,200 people in the world
have been
exposed to Tysabri in clinical trials and
post-marketing settings. (Abstract #P565)
In a small, ongoing study in 12 people taking Tysabri,
Dr. B. Khatri (Aurora St. Luke’s
Medical Center, Milwaukee) and colleagues
are exploring 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. Preliminary data from this
PLEX study suggest that the three courses of
plasma
exchange used in this study achieved a
significant reduction in Tysabri concentration.
So far
none of those treated has experienced an
increase in MS disease activity following plasma
exchange.
Further study is needed to determine whether
plasma exchange is an effective intervention
for PML. Funded by Biogen Idec, Inc and
Elan Pharmaceuticals. (Abstract #P576)
In recent years, continued research on Copaxone (glatiramer
acetate, Teva Pharmaceutical Industries) has
uncovered more information about how it
fights MS inflammation and more recently,
researchers have suggested that it may influence
brain
repair mechanisms. Along these lines, Dr.
C. Silva and colleagues presented work showing
that Copaxone generates immune T cells
that
are anti-inflammatory. In lab culture dishes,
these T cells produce growth factors that
can promote the generation of myelin-making
cells
(oligodendrocytes). To test their capacity
to promote myelin repair, they gave daily
injections of Copaxone to mice whose myelin
had been injured
in the spinal cord (lysolecithin-induced
demyelination). Treatment doubled the amount
of immature oligodendrocyte
repair cells (oligodendrocyte precursor
cells) normally stimulated in this situation.
Future
studies will focus on whether the elevation
of repair cells results in increased myelin
repair. Supported by Teva Pharmaceuticals
and the Multiple Sclerosis Society of Canada.
(Abstract
#P240)
Dr. D. Langdon and colleagues in the Betaseron® (interferon
beta-1b, Bayer Healthcare Pharmaceuticals
Inc) 16-Year Long-term Follow-up Study Group
administered
cognitive tests to 179 people who had originally
participated in the pivotal North American
clinical trial of Betaseron that led to
its approval. The investigators attempted to
correlate
the cognitive test results with the MRI
and EDSS (a disability measure) data obtained
for
the clinical trial 16 years earlier. They
found that people with higher EDSS scores (worse
disability) and greater amounts of disease
evidence on MRI scans had significantly
lower
cognitive test scores 16 years later. The
16-year followup study is funded by Bayer Schering
Pharma AG. (Abstract #P749)
Dr. K. Hawker (University of Texas Southwestern
Medical Center, Dallas) and colleagues
reported on an ongoing study of Rituxan® (rituximab,
Genentech and Biogen Idec) in 439 people
with PP MS**. The primary goal of the study
is
to determine the treatment’s effect
on time to disease progression as measured
by
the EDSS disability scale. The trial required
that all participants had signs of specific
antibodies (oligoclonal bands) in their
spinal fluid, which the investigators believe
may
account for the fact that 25% of participants
have MRI signs of active inflammation.
The investigators believe these demographics
increase
the possibility of detecting a therapeutic
effect for Rituxan, a treatment that acts
on immune system activity, specifically
B cells.
The trial is slated to go for 96 weeks.
Funded by Genentech, Inc. (Abstract #P553)
Findings on MS Development
In late-breaking news, Dr. F. Martinelli
Boneschi (Ospedale Maggiore, Milan) and colleagues
reported
having completed a scan of the genome (all
genetic material) in a group of 197 people
with primary-progressive MS, a course
experienced by about 10% of those diagnosed
with the
disease. They selected 20 genetic variations
for further
study, and compared them with genetic material
from 234 controls. One variation in the
HLA region (immune system genes associated with
MS) was more than twice as common in PP
MS
as in controls. They are now comparing
the results with scans of RR and SP MS, and
doing
other analyses of their findings. (Abstract
#114)
Dr. R. Zivadinov (SUNY Buffalo) and colleagues
reported on a study of 759 people with
MS, of whom 198 had a family history of MS.
Evaluating
MRI scans, the group found more severe
disease activity in those with a family history
of
MS, particularly those with first-degree
relatives with the disease. Further study is
necessary
to determine exactly how genetics affect
MS severity. (Abstract #P281)
Dr. Zivadinov also reported on cigarette
smoking and MRI findings in 368 people with
MS, of
whom 96 were active smokers and 32 were
former smokers. Measures of brain tissue volume
indicate
significantly lower volumes in smokers,
and a significant relationship between lower
volume
and higher average use of packs per day.
(Abstract #P607)
Recent studies have debated
the association between smoking and MS progression:
A 2005
Harvard University study showed an association
between smoking and risk of MS progression,
but a recent report from the Netherlands
found no such connection.
Dr. R. Magliozzi and colleagues in London
and Rome recently identified B-cell follicles,
sack-like structures, in the membrane that
surrounds the outer layer of the brain
(cerebral meninges) of people with SP MS, providing
further
insights into the role of B cells in the
immune attack. They found that these abnormal
structures
were associated with a younger age of diagnosis
and onset of disability, and a more aggressive
disease course. In a follow-up study, the
team analyzed areas of disease activity from
10
people with SPMS and ectopic B cell follicles,
10 people with SP MS and no B cell follicles,
and three controls. They found increased
damage to the cerebral cortex, the outer layer
of
the brain, in people who had SP MS and
follicles -- including decreases in nerve cells
and myelin-producing
cells, in association with a marked increase
in immune activity of cells called microglia.
Identifying these follicles in people with
SP MS may help predict a more aggressive
course of MS. (Abstract #45).
During a special session, Dr. F. Aloisi (Rome)
described further work exploring B cell
follicles and the possibility that their formation
could
be linked to an infection of B cells
with Epstein-Barr virus (EBV, the virus linked
to
infectious
mononucleosis and other disorders). Using
techniques to unravel the presence of EBV
in brain tissue
samples from people with MS, they showed
possible signs of accumulation of EBV-infected
B cells
and plasma cells in the follicles and
in MS lesions. They also showed evidence of
an
immune
attack toward EBV-infected cells in the
MS brain. Although previous studies have suggested
that exposure to EBV increases the risk
of
developing MS, possible evidence of the
virus’s
presence in brain lesions was lacking.
This study by an international team is bound
to
stimulate other investigators to attempt
to replicate their findings and to seek further
evidence of a direct link between EBV
and MS.
(Presentation #60, no abstract)
*RR MS –Relapsing-remitting
MS, a course of MS in which clearly defined flare-ups
are
followed by partial or complete recovery periods.
**PP MS – Primary-progressive MS, a slow
but nearly continuous worsening of disease
from onset.
***SP MS – Secondary-progressive MS,
an initial period of relapsing-remitting MS,
followed by a steadily worsening disease course
with or without occasional flare-ups or minor
recoveries.
‡
Relapsing forms of MS – Usually includes
individuals with relapsing-remitting MS and
also those with secondary-progressive disease
who still experience flare-ups.
Adapted from National MS Society website
Disponible en français.
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.
