Maybe this new Business Week article will help:
11/8/99 Bus. Wk. 111 (See Bold ... several places)
1999 WL 27296010
Business Week
Copyright 1999 McGraw-Hill, Inc.
Monday, November 8, 1999
Number 3654
Science & Technology: MEDICINE
ALZHEIMER'S: 'WE NOW HAVE CLEAR TARGETS'
Amgen's discovery of a key enzyme clears the way for further
breakthroughs
By Catherine Arnst, with Ellen Licking in New York and Amy Barrett in
Philadelphia
In late October, Amgen Inc. announced the breakthrough discovery of one of
the key triggers of Alzheimer's disease: an enzyme that sparks formation of
the plaque deposits that clog the brains of its victims. The finding was
reported one day before the annual meeting of the Society for Neuroscience,
where, in three days, attendees heard about more advances in Alzheimer's than
they had seen in decades. Elan Pharmaceuticals and SmithKline Beecham
announced results of their work on a plaque-forming enzyme. Other scientists
elaborated on the discovery only a few months ago of a different potential
plaque trigger. And dozens of research teams reported findings on new drugs,
diagnostic markers, and disease mechanisms. "This is a very, very exciting
time in Alzheimer's research," says Dr. Dennis J. Selkoe, director of the
Center for Neurologic Diseases at Brigham & Women's Hospital in Boston. "We
now have clear targets" for drugs that inhibit the disease.
Finally. Although Alzheimer's disease was identified in 1906, there is still
no effective long-term treatment for the degenerative brain disease. Even the
latest discoveries offer no guarantee--the research was done on mice, not
humans. And researchers are not sure if the plaque found in the brains of
Alzheimer's victims is a cause of the disease or merely a consequence--in
which case slowing its development would not bring a cure.
LAST FRONTIER. But there's no question that optimism is rife in the field. And
the need could not be more dire. Alzheimer's disease strikes 10% of people
over 65, and 50% of people over 85. Right now there are 4 million stricken
Americans--including former President Ronald Reagan--and the cost of caring for them is $80 billion to $100 billion a year. Over the course of about 10
years, patients gradually lose their memory and ability to function, sinking
into dementia and, finally, death. It is hard to diagnose, and there is no
treatment that attacks its underlying causes.
For the drug industry, Alzheimer's disease is the last frontier. "There
aren't many diseases that are completely untreated anymore," says Stephen M.
Scala, a pharmaceutical analyst at S.G. Cowen Securities Corp. "There are
probably 30 companies involved in some way in Alzheimer's." Scala estimates
that the U.S. market for Alzheimer's drugs, totaling $550 million now, will
reach $2.3 billion by 2003.
Despite massive research in recent years, there is only one drug currently
approved in the U.S. that is specifically aimed at Alzheimer's: Pfizer Inc.'s
Aricept, introduced in 1997. But Aricept and similar drugs seeking marketing
approval offer only modest relief from symptoms, delaying the inevitable
deterioration of the brain by 6 to 12 months.
No one yet knows why Alzheimer's strikes, but the brains of Alzheimer's
victims, unlike patients with standard dementia, become riddled with what's
called amyloid plaque--insoluble balls of protein that form in the regions
responsible for memory, emotions, and thinking (see table). Later in the
disease, tangles of protein develop inside brain cells. The plaque and tangles
trigger inflammation and oxidation that steadily damage brain cells.
Most researchers are focusing on identifying the mechanisms that spark
plaque buildup outside cells, because the internal tangles are much harder to
decipher. The plaque is created by a protein fragment called beta-amyloid, a
by-product of cell formation. Beta-amyloid is constantly being produced and
cleared from the brain, but in Alzheimer's victims disposal is inhibited.
Scientists believe the problem could lie with two enzymes involved in
production of the protein. They have named the hypothetical enzymes
beta-secretase and gamma-secretase.
SOLID DATA. On Oct. 22, Amgen caused waves of excitement in the Alzheimer's
world when it announced, in the journal Science, that it had found
beta-secretase. "It's immensely significant," says David B. Teplow,
assistant professor of neurology at Harvard Medical School. "The evidence
that this is beta-secretase is extremely solid."
And in April, Selkoe's lab at Harvard announced the discovery of a likely
gamma-secretase candidate. This enzyme is so closely linked to
gamma-secretase function, says Selkoe, that even if it isn't gamma secretase, blocking it could still slow plaque formation.
Many companies have been trying to stop plaque formation even without the
specific targets in hand. Cowen's Scala says Bristol-Myers Squibb Co. and Eli
Lilly & Co. will likely enter clinical trials next year with secretase
inhibitors. Elan Pharmaceuticals is trying to block plaque formation by
mobilizing the body's own immune system. Elan is seeking Food & Drug
Administration approval for a vaccine made from beta-amyloid that
significantly reduced plaque formation in genetically engineered mice.
Others are investigating anti-inflammatory drugs, to reduce the inflammation
that accompanies plaque formation. Population studies have long noted that
aspirin and other nonsteroidal anti-inflammatory drugs appear to reduce the
risk of Alzheimer's by 50%. Now, both Merck & Co. and Monsanto Co. are in
clinical trials for Alzheimer's with their COX-2 arthritis treatments, which
are in the same category as aspirin but have fewer gastrointestinal side
effects.
TRIALS IN PROGRESS. Clinicians are even more encouraged about the prospects
for treatment with estrogen. Again, population studies show that women with
low estrogen levels are at greater risk of developing Alzheimer's. That
suggests that estrogen "may give the brain a better means to fight off the
disease," says Dr. Claudia H. Kawas, clinical director of the Alzheimer's
Research Center at Johns Hopkins University. She says more than 30 clinical
trials are in progress to see if estrogen will delay onset of Alzheimer's
disease.
"If you could delay the average age of onset by just five years, the number
of new cases would be cut in half," says Steven H. Ferris, director of the
Silberstein Aging & Dementia Research Center at New York University. For a
disease this horrific, even small advances loom large.
Cause or Symptom?
Researchers know that insoluble amyloid plaque builds up in the brains of
Alzheimer's sufferers, slowly damaging and eventually killing brain cells. But
they don't know if the plaque buildup is a cause or symptom of the disease
HEALTHY BRAIN
In a normal brain, a protein fragment called beta-amyloid is constantly being
produced and cleared from the brain. It is essentially a waste product of a
larger protein that plays a key role in cell-to-cell adhesion. MILD ALZHEIMER'S
In Alzheimer's victims, the beta-amyloid becomes insoluble and can no longer
be sloughed off. The protein aggregates, first as filaments and then as
plaque, primarily in the areas of the brain that control memory, emotions, and
cognitive thinking.
SEVERE ALZHEIMER'S
As the plaque proliferates, it sets off inflammation that can cause severe
damage to cells. At the same time, tangles accumulate in the nerve cells,
causing more damage. The patient suffers progressive dementia and, eventually,
death.
At Long Last...Hope
Existing Alzheimer's drugs treat only symptoms, delaying deterioration by 6 to
12 months. But new drugs in development attack the underlying causes.
DRUG COMPANY COMMENTS
AN-1792 Elan Vaccine that prevents plaque buildup in mice.
Pharmaceuticals First human trials expected in early 2000.
GAMMA Eli Lilly/Scios Drug that blocks an enzyme that triggers
SECRETASE partnership plaque buildup. Human trials expected in
INHIBITOR early 2000. NEOTROFIN NeoTherapeutics A nerve growth factor that stimulates nerve
regeneration in the brain. Human clinical
trials are continuing.
VIVIQ Aventis Blocks damaging chemical reactions in brain
cells that impair cognitive function. Final
trials to start in 2000.
VIOXX Merck A COX-2 inhibitor approved for arthritis that
also appears to reduce brain inflammation. In
advanced trials for Alzheimer's.
CELEBREX Searle/Pfizer Another COX-2 inhibitor, also in advanced
trials for Alzheimer's.
PREMARIN American Home Estrogen replacement drug believed to protect
Products brain from plaque formation. Advanced trial
for Alzheimer's.
TEMPIUM Roche Holdings Limits brain-damaging free radicals. In ad-
vanced trials. Roche is expected to file for
approval by yearend.
DATA: SG COWEN SECURITIES CORP.
TABULAR OR GRAPHIC MATERIAL SET FORTH IN THIS DOCUMENT IS NOT DISPLAYABLE
Photograph: FIRST PATIENT: Ronald Reagan, shown in 1998, was diagnosed as a victim DAVID ROHMER/LIAISON AGENCY
---- INDEX REFERENCES ----
COMPANY (TICKER): Amgen Inc. (AMGN)
NEWS SUBJECT: World Equity Index (WEI)
INDUSTRY: Biotechnology; Medical & Biological Technology (BTC MTC)
Word Count: 1100
11/8/99 BUSWK 111
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