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ARRESTING ALZHEIMER’S
Drugs that fight milder memory loss may prevent its onset.
By: Naomi Freundlich
Business Week, June 112001
A new front has opened in the battle against Alzheimer’s disease. Coming
up with a cure for this dreaded form of dementia has proven devilishly
hard, since by the time victims develop Alzheimer’s, their brains are
usually too damaged for any treatment to do much good. So drug companies
are increasingly turning their attention to a different class of
patients-those who suffer from noticeable memory loss but otherwise
function normally. The theory is that treating patients with this
condition, known as mild cognitive impairment (MCI) might delay or deter
full-blown Alzheimer’s.
MCI sufferers show no deterioration in IQ scores but they experience
“forgetfulness of a significant nature,” such as failing to recall
conversations held a short time before, says Dr. Ronald C. Petersen,
director of the Alzheimer’s Disease Research Center at the Mayo Clinic
in Rochester; Minn. This is a more significant memory loss than forgetting
a name or where you left the car keys. Within six years of a diagnosis for
MCI, some 80% of such patients progress to Alzheimer’s.
Consequently, the Food and Drug Administration has signaled its
willingness to overhaul its own criteria for judging brain-enhancing
drugs. On Mar.13, an FDA advisory group ruled that experimental
Alzheimer’s treatments can win approval if they improve memory function
in people with MCI, even if they don’t alter the course of Alzheimer’s
itself. This could mean a potential windfall for drug companies. There are
currently 4 million Americans suffering from MCI and another 4 million
with Alzheimer’s disease, says Vincent Simmon, CEO of Cortex
Pharmaceuticals Inc., a neuroscience company in Irvine, Calif. Those
numbers will go up as the baby boomers age. In 2000, 35 million Americans
were 65, and by 2025, there will be 63 million. Alzheimer’s strikes
about 10% of people over 65.
The National Institutes of Health is leading the way in MCI research. In
1999, its National Institute on Aging announced it would sponsor a
three-year; multicenter study over 700 MCI sufferers ranging in age from
55 to 90. This trial is designed to see if Pzifer Inc.’s leading
Alzheimer’s drug, Aricept, or vitamin E, can delay the onset of
Alzheimer’s or other forms of dementia. Other NIH-sponsored trials are
testing estrogen and the popular anti-inflammatory drugs that are known as
cox-2 inhibitors for the same purpose. If such treatments can delay the
onset of Alzheimer’s disease just for one year “it could help between
220,000 to 440,000 people and save between $10 Billion and $billion
annually,” says Dr. Leon Thal, head of the Alzheimer’s Disease
Research Center at the University of California at San Diego.
It will be at least three years before the NIH trials produce concrete
results, and some scientists are already questioning the value of the
Aricept trial. “Pzifer is dying to use Aricept on MCI,” says Harry
M.Tracy, publisher of the Newsletter NeuroInvestment. “But there is a
big question about whether it will work.” The drug is one of three
Alzheimer’s treatments on the market. All of them block the breakdown of
a brain chemical called acetylcholine that is important in memory and
other intellectual functions. But there is no proof the loss of
acetylcholine plays as large a role in MCI as it does in Alzheimer’s
patients. And these drugs aren’t even that effective against
Alzheimer’s-they help less than half of all Alzheimer’s patients, and
then for a peiod of only a few months or at most two years.
The problem, it seems, is that by the time a patient develops
Alzheimer’s the damage is done. The disease is caused by a steady
accumulation in the brain, over many years, of an insoluble protein called
beta-amyloid. As it accumulates, it forms brain clogging plaque. Victims
eventually lose all mental and physical functions, until they die, after
about 10 to 12 years.
New drugs in the pipeline aim either to boost the brain’s ability to
form memories despite the plaque; or to slow the plaque buildup. In the
category are a group of drugs called ampakines, developed by Cortex in
partnership with the French company Servier, that increase the activity of
brain chemicals important to memory formation. Cortex is testing one of
its ampakines in a small study of Alzheimer’s patients. The company is
planning a larger MCI trial with Servier for later this year.
Improved memory function is also the goal NeoTherapeutics Inc. in Irvine,
calif. Its lead experimental drug, Neotrophin, stimulates the production
and release of growth factors in the brain’s memory centers. These
growth factors then coax neurons into making new connections with other
nerve cells. Neotrophin has been tested more than 1,000 Alzheimer’s
patients, with mixed results. Still, NeoTherapeutics President Rajesh C.
Shrotriya says: “We believe that Netrophin could have an effect in
normal memory loss.” Once the drug is approved for Alzheimer’s he
plans to begin testing it in patients with MCI.
END RUN
The formation of memories, though, is a murky process. As researchers
in this field feel their way along, they are testing a number of
therapeutic approaches intended to aid the development of memories. Memory
Pharmaceuticals Corp., a New York neuroscience company, is developing
drugs that will help the brain convert transient short-term memories into
stable long-term potentiation, is compromised in the aging brain and in
Alzheimer’s victims. Axel Unterbeck, president of Memory
Pharmaceuticals, says the company has identified several promising drugs
in hopes to start trials with Alzheimer’s patients in two years.
Memory Pharmaceuticals is also trying to do an end run around the disease,
with experimental drugs that enhance the activity, and perhaps the growth,
of undamaged neurons in the brain’s memory centers. This approach could
have wide utility in treating memory problems associated with dozens of
diseases, including the normal forgetfulness linked to aging. “It’s a
very important notion that even if companies succeed in prohibiting
amyloid production, the patient will still need treatment of memory
problems,” says Unterbeck. “We see using one drug that affects disease
progression and another that improves function and keeps the patient at
home.”
Then there are the plaque-attackers. Several groups are working on
vaccines that would stimulate the immune system to slough off the plaque
deposits that lead to Alzheimer’s. The leading candidate is from Elan
Corp. in South San Francisco. In one test, Elan’s vaccine caused a 70%
reduction in amyloid plaques in the brains of mice genetically engineered
to develop Alzheimer’s. Elan, in partnership with American Home
Products, is now running early stage safety trials of its vaccine in
people with advanced Alzheimer’s disease. “If the immunization works
in Alzheimer’s patients, we will move to MCI very rapidly,” says Dale
B.Schenk, vice-president for research at Elan.
Beyond vaccines are efforts by Bristol Myers Squibb, Eli Lilly, and Elan
to develop compounds that block the enzymes that help cause plaque. Other
drugs under development are likewise meant to interfere with the process
of plaque formation.
In three to five years, there may be more options for treating MCI and new
methods for slowing the onset of Alzheimer’s. Researchers are also
trying to devise ways of detecting who is at risk for Alzheimer’s years
before it becomes apparent. In the end, the best chance of “curing”
Alzheimer’s may be targeting simple forgetfulness.
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