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Alzheimer's - and the
Pharmaceutical industry
Medicines For Alzheimer's In The
Development Pipeline
Medicines acting on acetylcholine
Several other AChE inhibitors are in clinical trial and one
in preclinical development. The most advanced is TAK-147 (Takeda),
which is one of a related group of molecules designed to bind
to the enzyme acetylcholine esterase and block its action.
TAK-147 appears to survive for long periods in the brain.
It also has a beneficial effect on some other brain pathways
and stimulates brain energy metabolism which is depressed
in Alzheimer's.
Finally and unexpectedly, it was found to stimulate the growth
of neurons that use ACh and in that respect behaves like a
naturally-occurring nerve growth factor (NGF). Takeda speculates
that TAK-147 will not only improve the symptoms of Alzheimer's,
but also prevent or slow its progression. With this interesting
range of properties, the outcome of early clinical trials
that have now started will be keenly awaited.
Another AChE inhibitor at an earlier stage of development
is huberzine A, originally derived from a Chinese herb called
Huperzia serrata. Improvements in cognitive performance have
been reported in several small trials in China. Herbal remedies
are currently available containing this compound, even though
adequate toxicity studies have not yet been done. Recent reports
of tacrine-huberzine hybrid molecules which bind very tightly
to AChE have also appeared and may be developed further in
the future.
Still at the preclinical stage is CHF2819 (Chiesi Farma),
an orally active AChE inhibitor. Model studies show that it
significantly increases ACh levels in ageing animals. A role
in the treatment of Alzheimer's is possible, but it is unclear
whether it will have advantages over currently available medicines.
As explained above, the ACh esterase inhibitors donepezil,
galantamine, rivastigmine and tacrine all block the breakdown
of acetylcholine. An alternative approach would be to boost
its levels.
One simple strategy to achieve this has been to give dietary
supplements of the starting materials from which ACh is made,
such as lecithin, which is rich in choline, or choline itself.
The benefits were at best marginal, though a small placebo-controlled
clinical trial of a molecule that gives rise to choline, called
citicholine, did give some improvements in word and object
recall memory tests. Despite this modest outcome, it is clear
that alternative approaches are needed.
Medicines acting on M and N acetylcholine
receptors
Several companies have investigated the role in Alzheimer's
of muscarinic or M receptors. If M receptors are stimulated,
extra ACh is released from internal stores inside neurons,
thus providing short-term improvement. Their stimulation also
causes the cells to produce more of the harmless beta-amyloid,
rather than the toxic BAP42 found in plaques. It is just feasible,therefore,
that medicines of this type will slow progression as well
as treat some of the symptoms. Five types of M receptor have
been discovered, numbered M1 to M5. They are found in various
parts of the body outside the brain and their stimulation
gives rise to symptoms such as sweating, salivation, nausea
and vomiting, which would be unwanted in a medicine. The key
is to find molecules that act only on M receptors in the brain.
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Placebos
A placebo is a dummy treatment
with no activity against a patient's condition
and administered to a control group in a clinical
trial. It is given to a proportion of the people
taking part, so that comparisons can be made with
the active compound that is being tested. Neither
participants nor the doctors know whether they
have the placebo or the real thing - called a
double-blind trial. In order to be considered
effective, the experimental treatment must therefore
produce better results than the placebo.
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Most research has focused on the M1 receptor, and at least
ten molecules that stimulate it have been studied. Sadly,
several of them had unwanted side effects and have been discontinued
at the clinical trial stage, though two, Boehringer Ingelheim's
talsaclidine, and Pfizer's CI-1017, are still in development.
The former successfully completed Phase 1 safety studies and
is now in Phase 2, but little information has been released
about its efficacy. CI-1017 appeared to improve spatial memory
in experimental models. A third compound of this type is in
development by Schering-Plough. It appears to be an M2 stimulator,
but nothing has yet been revealed about its activity or tolerance.
The nicotinic (N) receptors have been less explored, but
three compounds still in development are GTS-21 (Taisho),
SIB-1553A (SIBIA Neurosciences), and nefiracetam (Daiichi).
Galantamine may also act partly in this way.
The first was developed by chemical modification of a toxin
from a marine invertebrate. Chemically, it is called an alkaloid
and has been shown to bind to the N receptor sub-type found
most abundantly in the cerebral cortex and hippocampus which
are most affected in Alzheimer's. Interestingly, GTS-21 can
also protect neurons against damage by amyloid peptides, at
least in cell culture, which implies that this receptor has
a protective role. The compound is active in several model
systems and produced beneficial effects in psychological tests
when given to healthy volunteers in a Phase 1 trial.
SIB-1553A also binds to N receptors and in so doing promotes
ACh release. It is much less toxic than nicotine itself and
is considered to have interesting potential. Nefiracetam works
slightly differently and appears to stimulate electrical current
flow in N receptors. This in turn causes increased in nerve
signalling in the hippocampus.
These medicines acting on the acetylcholine M and N receptors
are a good illustration of the complexities faced by pharmaceutical
scientists when trying to find truly selective molecules.
Without selectivity, these compounds will always produce unwanted
and in many cases unacceptable side effects.
Other receptor targets
Several other sites in the brain, thought to have a role
in memory, rational thought and behaviour, are being explored
using experimental medicines in Alzheimer's, including receptors
known as NMDA, AMPA, 5-HT and GABA.
One medicine which acts on the NMDA (N-methyl-D-aspartate)
receptor is memantine, already on the market in Germany for
Alzheimer's and now being developed by Merz in collaboration
with Lundbeck for wider distribution in Europe. Memantine
has been tested in groups of people with moderate to severe
Alzheimer's or vascular dementia and appears to benefit both
types of individual when judged on clinical and behavioural
rating scales.
Ampakine or CX516 (Cortex) stimulates nerve signals in AMPA
receptors which are found in similar parts of the brain to
NMDA receptors. It has been reported to improve memory performance
in elderly subjects and has now progressed to Phase 2 clinical
trials. Its ability to prevent people with mild memory impairment
progressing to Alzheimer's is being assessed.
Nerve pathways in the brain that depend on the chemical messenger,
5-hydroxytryptamine (5-HT) also decline in Alzheimer's, and
some companies have explored medicines that act on 5-HT receptors.
Aventis has a medicine called M100907B in Phase 1 trials which
acts on 5-HT2 receptors. It might be of use in improving some
of the behavioural and psychological symptoms of Alzheimer's.
At a similar stage of development is GlaxoSmithKline's SB271046,
a 5-HT6 receptor blocker, which has shown promise in animal
models that involve learning and decision making steps.
A collaboration between Pfizer and the Neurogen Corporation
in the USA has developed medicines that act on the GABA (Gamma
Amino Butyric Acid) receptor. It has been known for some time
that medicines that stimulate GABA receptors can make memory
worse. Pfizer and Neurogen have used their expertise in this
area to develop medicines that do exactly the opposite, namely,
enhance memory. One, NGD 97-1, worked well in model systems,
and it is anticipated that it will help memories form and
increase attentiveness. Phase 1 trials have started in Europe,
and an application to start Phase 2 trials has been filed
in the USA.
Non-steroidal anti-inflammatory agents
(NSAIDs) in Alzheimer's
Sites of inflammation can often be recognised because specialised
cells collect in them. In the brains of people with Alzheimer's,
active inflammatory cells, called microglia, collect around
the amyloid plaques. Here they make substances which are directly
harmful to neurons in the vicinity, and may also hasten the
deposition of amyloid. Hence, anti-inflammatory medicines
such as the steroids or NSAIDs developed initially for arthritic
conditions may be beneficial for people with Alzheimer's by
damping down the inflammatory process.
A recent trial in Alzheimer's using the steroid prednisolone
was disappointing, but trials in the 1990s with two NSAIDs,
indomethacin and diclofenac, suggested that both slowed the
loss of reasoning power. Unfortunately, many elderly people
could not tolerate the side effects in the stomach and dropped
out of the trials. Another NSAID, ibuprofen, is being examined
in Phase 3 trials by several companies, including Wyeth, Pharmacia,
and Bristol-Myers Squibb.
Some of the more selective NSAIDs called cyclooxygenase-2
(COX-2) inhibitors may have fewer side effects on the stomach.
They may also be more relevant to the disease process, because
it has been shown that the amount of COX-2 in the brains of
people with Alzheimer's is double that in well people, and
the quantity present correlates with amyloid plaque density.
Three COX-2 inhibitors are being assessed in trials: celecoxib
(Pharmacia), rofecoxib (Merck Sharp & Dohme), and GW253035
(GlaxoSmithKline). The first two, already available for other
types of inflammation, are being tested both for their ability
to prevent Alzheimer's and to slow down the decline in the
first stages of the illness. First trial results with celecoxib
were not encouraging, but these are early days.
Compounds acting on Reactive Oxygen
Metabolites
All cells generate by-products as they consume food for energy
and growth. Some of these are very reactive forms of oxygen
called Reactive Oxygen Metabolites (ROMs) which can damage
or even kill cells unless they are trapped and neutralised
by the body. Sometimes the body's mechanisms to neutralise
them are overwhelmed and if this happens, ROMs can help trigger
or aggravate conditions such as arthritis, cancers, heart
disease, and strokes, and also accelerate the ageing process.
Several theories have been proposed which suggest that ROMs
contribute to Alzheimer's and considerable efforts have been
made to develop medicines that will inactivate them before
they can cause damage. One of the few accurate biological
measures of ageing is hearing loss. This happens because of
damage caused by ROMs to the energy generating 'factories'
called mitochondria in the cells of the inner ear. A natural
substance that can protect against this and even repair damage
in model systems is a called acetyl L-carnitine (ALC, Sigma-Tau
Pharmaceuticals). On the strength of this type of evidence,
ALC has progressed into Phase 3 trials in people with early-onset
Alzheimer's. Vitamin E, for which hints of activity have been
reported, also acts partly in this way.
Plant extracts have traditionally been a part of human medication.
Reports from the New York Institute for Medical Research show
that a standardised extract of the leaves of the ginkgo or
maidenhair tree (Ginkgo biloba), called EGb 761, improved
thought and reasoning processes in Alzheimer's as measured
on the ADAS-COG scale. The effects have been confirmed in
trials. These extracts contain several substances that have
anti-ROM activity and were able to stimulate electrical signals
in the brain. Ginkgo extract has been approved in Germany
for the treatment of dementia for some years, but has not
been introduced elsewhere.
Another modified natural product, a dendrotoxin present in
the venom of the green mamba snake, has also been proposed
as the basis for new Alzheimer's medicines. Basic research
has shown that it boosts the passage of signals between nerves
by altering the movement of ions such as potassium. Potassium
has an important role in the brain and helps, indirectly,
to regulate the release of chemical messengers such as acetylcholine.
However, extensive clinical trials will be necessary to confirm
whether these natural products are truly effective.
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