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Scientist Think Alzheimer’s Vaccine Looks Promising
May 9, 2005 – Using a vaccine to train the immune
system to fight back against Alzheimer’s still may be a possibility,
according to researchers who studied patients that participated in
studies that were stopped in early 2002 after brain inflammation in some
patients. Participants in the test who received the beta amyloid protein
in their vaccination performed better on memory tests than those who
received a placebo injection, according to follow-up studies.
Scientist are already recruiting new participants
for a clinical trial to test a new Alzheimer’s immunotherapy vaccine
strategy. The tragic brain disorder affects 4.5 million Americans and
surveys have shown it is the disease senior citizens fear most.
The conclusions of the two new papers was published
in the journal Neurology by an international team of researchers who
vaccinated hundreds of Alzheimer’s disease patients with beta amyloid, a
protein that builds up in Alzheimer’s-affected brains.
Although the study was stopped in 2002 after a few
participants developed brain inflammation, the researchers continued to
monitor the patients for up to a year after their last injection. The
new papers, including one led by the University of Michigan Health
System neurologist who headed the study’s safety committee, summarize
the results of that effort.
Even as those results are published, doctors at U-M
are preparing to recruit participants for a phase II clinical trial to
test a new Alzheimer’s immunotherapy vaccine strategy that has been
through a phase I safety trial. The phase II study, which aims to
stimulate an immune attack against beta amyloid without raising brain
inflammation risk, is being conducted at 30 centers in the United States
and dosing has already begun at some sites. All the trials have been
funded by Elan Corporation and Wyeth Pharmaceuticals.
Results from the interrupted trial show that on the whole, study
participants whose immune systems mounted a response against beta
amyloid performed significantly better on a series of memory tests than
those who received a placebo injection.
Brain scans also showed that patients who had an
immune response experienced a decrease in brain size, possibly
indicating the removal of built-up protein due to an immune system
attack. A smaller group of immune responders also had a decrease in
levels of a protein called tau in their spinal fluid, compared with
participants who received placebo — possibly indicating a slowing in the
death rate of their brain cells.
“The idea of inducing the immune system to view
beta amyloid as a foreign protein, and to attack it, holds great
promise,” says Sid Gilman, M.D., F.R.C.P., the first author on one of
the new papers and the head of the Data Safety Monitoring Board for both
clinical trials. “We now need to see whether we can create an immune
response safely and in a way that slows the progression of Alzheimer’s
disease and preserves cognition.”
Gilman is the William Herdman Professor of
Neurology at the U-M Medical School and director of the Michigan
Alzheimer’s Disease Research Center, one of 32 in the country funded by
the National Institute on Aging.
Nancy Barbas, M.D., M.S.W., a U-M neurologist who
will soon begin recruiting participants for the new trial, calls the
approach, known as immunotherapy, exciting. “Safety is paramount, given
the experience with the last trial, and the new study is designed to be
extraordinarily cautious and conservative,” she says. “But if we can
show an effect, it will mean we’re that much closer to giving patients
and their families better options for treatment.”
Rather than injecting participants with beta
amyloid itself, the new trial is based on injections of humanized
antibodies against part of the beta amyloid molecule. The antibodies
should help trigger the immune system to attack beta amyloid, but will
be cleared by the body soon after injection. That means a series of six
injections to “remind” the body to attack beta amyloid.
As in the previous study, participants will be
randomly assigned to receive either antibodies or a placebo; neither
they nor the researchers will know what they got until the 27-month
study ends. The new study will enroll 180 adults between the ages of 50
and 85 who have a diagnosis of probable Alzheimer’s and a caregiver who
can bring them to frequent appointments for brain imaging,
neuropsychological testing and blood tests. Some participants will have
additional blood tests or spinal fluid tests; they will also have a
slightly higher chance of getting antibodies.
Gilman explains that the concept of vaccinating
against beta amyloid was first proposed by scientist Dale Schenk. In the
late 1990s, Schenk and his colleagues showed that vaccination from birth
could prevent mental decline in mice that had been bred to develop
Alzheimer’s-like disease. They and others also showed that older mice
receiving the vaccine appeared to regain cognitive function.
The exciting animal research results led to a Phase
I trial in humans with Alzheimer’s disease that showed no ill effects —
and then the Phase II trial that was stopped early.
“With the full agreement of both sponsors, Elan and
Wyeth, we halted the study as soon as we heard of the first few cases of
meningoencephalitis, or brain inflammation,” says Gilman, referring to
the trial’s Data Safety Monitoring Board of independent experts not
involved in treating trial participants. “But for a year afterward, we
kept participants and researchers blinded to which patients had received
beta amyloid and which had received placebo.”
In all, 59 of the 300 participants who received at
least one injection of beta amyloid developed significant quantities of
antibodies against it in their blood. All but three of these 59
patients, who were called “antibody responders,” had received at least
two injections before the study was stopped; nine of them had received
three injections. Thirteen of the 59 developed some level of
encephalitis, as well as five of the patients whose immune systems did
not react as strongly.
Although the study showed no statistical difference
between the placebo and beta amyloid groups in results on five tests
often used in patients with Alzheimer’s disease and other dementias,
there were significant differences on a battery of other tests that
measure memory, executive function and verbal ability. The difference
reached statistical significance in immune responders compared with
patients who received placebo.
Spinal fluid samples taken from 21 of the
participants in the study before it was stopped also reveal some
intriguing hints. The 11 immune responders had a significant decline in
levels of the tau protein, a structural protein considered a hallmark of
cell death in the brain, when compared with 10 participants who received
placebo.
Also encouraging, but not conclusive, is evidence
from autopsies conducted on Phase I and II trial participants who have
died in the years since the studies were completed or stopped, Gilman
says. “Three participants died of causes unrelated to the vaccination,
two of whom had developed encephalitis and one other did not develop
encephalitis. All had large patches of their brains where beta amyloid
had apparently been cleared out — the tangles of tau protein were still
visible,” he explains.
The first three cases from the Phase II trial have
been published in separate papers. The fourth case of a patient in the
Phase I trial was recently presented at an international meeting. The
participant received four injections of beta amyloid and had evidence in
the brain tissue of immune system cells (microglia) removing beta
amyloid protein — a sign of an active immune response.
The MRI images taken of study participants before
and after their injections also showed shrinking of brain tissue that
was more pronounced in the 45 immune responders than in 57 placebo
patients. “This was the opposite of what we expected, and it’s exciting
because it was associated with relative preservation of memory,” says
Gilman. “It may be that beta amyloid was taken out of the brain as a
result of the immune response, and that the protein carried water with
it, causing further shrinkage.”
The new clinical trial builds on the interrupted
study’s design, Barbas says, by including MRI and electrocardiogram
exams, blood and urine tests, regular vital sign exams, and tests of
memory and thinking ability. All of the injections will be in the first
year, with the second year for follow-up exams.
U-M is not yet recruiting participants for this
study, but is taking names of those people who might want to be
contacted when recruitment opens. U-M researchers are also seeking
people who might want to learn about other opportunities to participate
in Alzheimer's disease and dementia research at U-M. Call 734-647-7760
or email
neuro-dementiatrials@med.umich.edu.
The first authors of the two papers in Neurology
are neurologists who are independent of the two sponsoring companies.
Gilman is first author of one paper; the other first author, on the
paper detailing MRI results, is Nick Fox of the Dementia Research Centre
at the Institute of Neurology in London’s National Hospital for
Neurology and Neurosurgery.
Gilman was reimbursed by Elan Corporation for his
time reviewing safety data for the interrupted clinical trial, and has
the same relationship for the purposes of the new clinical trial. He
receives no other funds and no stock or stock options from the sponsors.
Other authors of the papers include Elan employees and researchers who
have received honoraria from, or hold stock in, Elan and Wyeth.
Citation: Clinical effects of beta A immunization
(AN1792) in patients with AD in an interrupted trial, Neurology ; 64:
1553
Effects of beta A immunization (AN1792) on MRI
measures of cerebral volume in Alzheimer disease Neurology ; 64: 1563
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