Professional Documents
Culture Documents
Background Paper
Alzheimer Disease
Opportunities to Address Pharmaceutical Gaps
6.11-1
Table of Contents
1.
2.
Summary......................................................................................................................................3
Introduction.................................................................................................................................4
Cause.............................................................................................................................................4
3. Size and Nature of Disease Burden.........................................................................................4
Incidence and Prevalence............................................................................................................4
4. Control Strategy..........................................................................................................................9
Diagnosis......................................................................................................................................9
Research Directions in Diagnosis and Evaluation.................................................................11
Management...............................................................................................................................11
Pharmacological Therapy Review for AD...............................................................................11
Psychiatric Management of Non-Cognitive Symptoms........................................................14
Affordability and Feasibility.....................................................................................................15
5. Major Problem and Challenges for Disease Control:
Why Does the Disease Burden Persist?.................................................................................15
Risk Factors.................................................................................................................................16
Trends..........................................................................................................................................18
6. Past/Current Research into Pharmaceutical Interventions of AD....................................18
Drugs for Disease Modification...............................................................................................18
Drugs for Prevention and Disease Modification....................................................................19
7. Current Pharmaceutical Product Pipeline for AD Treatment.......................................21
Research into Emerging Technologies.....................................................................................22
Europe and the Fifth Framework Program for Alzheimers Disease...................................22
8. Opportunities for Research into New Pharmaceutical Interventions.............................23
Gaps Between Current Research and Potential Research Issues that Could Make a
Difference....................................................................................................................................24
9. Barriers to Closing the Alzheimer Pharmaceutical Gap....................................................25
10. European Union Funding Opportunities for AD.................................................................26
11. Conclusion.................................................................................................................................27
10 References..................................................................................................................................29
Annexes
6.11-2
1. Summary
Alzheimer disease is a neuro-degenerative disease of the brain that causes changes in brain
function. AD usually affects people over the age of 65 years, with a progressive decline in
memory, thinking, language and learning capacity. Age is the strongest predictor for the
development and progression of AD and with the rapidly aging population of our society,
AD clearly poses a major health problem. An estimated 5-10% of the population aged 65
years and over and 40% of the population greater than 85 years of age are likely to be affected
by AD.
The pathophysiology of AD is related to the injury and death of neurons, especially in the
areas of the brain that are involved with memory and learning. Alzheimer disease is the most
common dementia, accounting for 50%-75% of the total, with a greater proportion in the
higher age ranges. There are nearly 18 million people with dementia in the world today. The
number of people with dementia is expected to increase steadily over the next 25 years. By
2025, there will be about 34 million people with dementia in the world.
There are currently no specific tests that may positively confirm the diagnosis of AD. AD
may be diagnosed on physical and neurological exams, and checking for signs of intellectual
impairment through standard tests of mental function. Definitive changes found in the brain
of affected AD patients are microscopic and can be seen only when a sample of brain tissue is
removed and examined, usually on autopsy.
At present, there is no cure for AD, or any pharmacologic therapy that can delay its onset
or affect the pathophysiology of the illness. The primary goals of treatment are to maximize
the patients ability to function in daily life, maintain quality of life, slow the progression of
symptoms, and treat depression or disruptive behaviors. The current pharmacologic
therapy for AD only provides symptomatic relief for a short period of time, six to eighteen
months.Error: Reference source not found , The only drugs approved in the US and several
parts of Europe for treating AD are cholinesterase inhibitors and the NMDA antagonist,
memantine. These drugs do not affect the pathology or progress of AD.
Management of AD is complex and clinicians and caregivers are confronted with numerous
challenges in managing the AD. Some of these include employing unique social and
environmental interventions; knowledge and use of increasingly sophisticated medications,
and providing individualized therapy to patients, working with care takers or varying
systems providing care.
Continuing efforts are still required. This includes developing medicines that would slow
progression, halt, or prevent AD from occurring. Additionally, challenges for clinical services
include early diagnosis, and intervening early with the most appropriate and effective
medicine. Furthermore, validated therapeutic targets need to be identified, and better animal
research models are needed which reflect the disease. Biotech and major industry also need
to recognize the potential market opportunities for AD and despite the high risk, the rewards
for effective medicines that could delay or halt the disease are huge. The high risks associated
6.11-3
2.
Introduction
Dementia is a generic term that describes the cognitive decline in brain function 1. There are
several causes of this condition, such as Alzheimer disease, AIDS, head injury etc. Some
conditions that cause dementia can be reversed, and others cannot. The two most common
forms of dementia in older people are Alzheimer disease and multi infarct dementia
(sometimes called vascular dementia). These types of dementia are irreversible. 2 Alzheimer
disease (AD) is the most common form of dementia; it accounts for 64 per cent of all
dementias.3
AD is characterized by a progressive decline in cognitive function. AD usually affects people
over the age of 65 years, with a progressive decline in memory, thinking, language and
learning capacity. AD should be differentiated from normal age-related decline in cognitive
function, which are more gradual and associated with less disability. 4 AD often starts with
mild symptoms and ends with severe brain damage. People with dementia lose their abilities
at different rates. On average, AD patients live from 8 to 10 years after they are diagnosed,
though the disease can last for as many as 20 years.Error: Reference source not found, 5
Cause
The pathophysiology of AD is related to the injury and death of neurons, especially in the
areas of the brain that are involved with memory and learning. Patients affected with AD,
show two specific microscopic changes-senile plaques (abnormal deposits of a protein called
amyloid) and neurofibrillary tangles (abnormal spiral filaments in neurons). Through some
unknown mechanism, senile plaques and neurofibrillary tangles prompt the injury and
death of neurons, and this subsequently produces the intellectual and behavioural
symptomatic changes evident in AD. 6
Currently, theories about the development of AD have focused on how the death of neurons
affects levels of essential brain chemicals called neurotransmitters. When injured neurons in
the hippocampus and cortex die, there is a corresponding drop in neurotransmitter
acetylcholine. Error: Reference source not found Other neurotransmitter systems are also
affected later in the disease e.g. glutamate, serotonin.
3.
2000000
World-F
1500000
World-M
1000000
EU25-F
EU15-F
500000
EU25-M
EU15-M
EU10-F
EU10-M
0
0-4
80+
Figure 2 plots the burden of disease for Alzheimer disease for the different EU and World
regions as a fraction of all DALYs (both acute and chronic conditions) for different age
groups. Alzheimer`s disease increases to nearly 20% of the total disease burden (both acute
and chronic) among women in the EU15.
6.11-5
Figure 2.
The mode of onset and subsequent course of dementia depend on the underlying etiology.
Alzheimer disease has an insidious onset and slow decline in brain function, while vascular
dementia is characterized by a more acute onset and stepwise decline. The effective
management of dementia is a function of the underlying pathology and of the availability
and timely administration of effective treatment Error: Reference source not found
Dementia Worldwide 8:
There are nearly 18 million people with dementia in the world today. The number of
people with dementia is expected to increase steadily over the next 25 years (See also
Figures 1 and 2 showing age distribution). By 2025 there will be about 34 million people
with dementia in the world By 2025, 71% of people with dementia will live in developing
countries.
The overall incidence of dementia increases with age at 1% per year. This estimate is
lower for men and people of African or Asian origin.Error: Reference source not found
AD is more prominent in Europe and North America, and in developing countries
dementia appears to be rare. These differences are difficult to explain and may be a result
of poor diagnosis and survival bias due to high death rates at all ages.Error: Reference
source not found
6.11-6
AD prevalence among those older than 60 years is about 5% for men and 6% for women.
With a growing aging population, these numbers are expected to increase rapidly over
the next 20 years. Error: Reference source not found
Dementia in Europe 9
Work from the European Community Concerted Action on the Epidemiology and
Prevention of Dementia group (EURODEM) allows countries participating in the study to
estimate the number of people likely to be affected by dementia-provided that the
accurate population statistics are made available.
EURODEM is able to provide data on the prevalence of moderate to severe dementia and
determine prevalence rates for men and women in 9 different age groups. The study
includes people living with dementia in institutions, nursing homes, residential care as
well as those living at home. The study was only based on diagnosed cases of dementia,
and the report acknowledges the problems related to this, since many people fail to get
diagnosed and are therefore excluded.
Data for this study comes from the following European countries: Germany, Finland,
France, Italy, The Netherlands, Norway, Portugal, Spain, Sweden, and UK.
Table 1. EURODEM Prevalence Rates for Men and Women in Nine Different Age
Groups for Dementia (1980-1990 Findings)Error: Reference source not found
Age group
30-59
60-64
65-69
70-74
75-79
80-84
85-89
90-94
95-99
Male
0.16%
1.58%
2.17%
4.61%
5.04%
12.12%
18.45%
32.1%
31.58%
Female
0.09%
0.47%
1.10%
3.86%
6.67%
13.50%
22.76%
32.25%
36.00%
6.11-7
652,600
63,700
17,100
41,800
775,200
55%
20%
15%
5%
5%
Dementia in Japan 10
By the end of Sept. 2003, there were 20,561 people over 100 years old in Japan, of which
84.6% were female. Prevalence of dementia increases with age with a prevalence of 1.5%
in the group aged 65-69 and 27.3% in the group aged 85 and over. In Japan dementia of
vascular type is more prevalent than Alzheimer type. Estimates of vascular versus
Alzheimer dementia in Japan are probably distorted because of cultural factors, i.e. it is
more acceptable to have a vascular disorder than a mental disorder.
Dementia in CanadaError: Reference source not found
There were an estimated 83,200 new cases of dementia in 2001. By 2011 new cases of
dementia are expected to reach 111,600 per year. Alzheimer disease affects 1 in 20
Canadians over age 65. By 2031: over 3/4 million Canadians are expected to have
Alzheimer disease and related dementias.
Dementia in the US 11
An estimated 4.5 million Americans have Alzheimer disease, according to data from 2000
U.S. census. This data also shows that by 2050, the number of Americans with Alzheimer
disease could range from 11.3 million to 16 million.
National direct and indirect annual costs of caring for individuals with Alzheimer
disease are at least $100 billion, according to estimates used by the Alzheimers
Association and the National Institute on Aging.
Alzheimer disease costs American business $61 billion a year, according to a report
commissioned by the Alzheimers Association. Of this amount, $24.6 billion covers
Alzheimer health care and $36.5 billion covers costs related to caregivers of individuals
with AD, including lost work productivity, absenteeism and worker replacement.
6.11-8
4.
Control Strategy
AD disease is a complex disease and its management is often challenging. Personality and
behavioural changes, and the eventual inability to perform activities of daily living lead to
dependence. As functional impairment deteriorates, health care utilization increases until
patients are forced to become institutionalized for around the clock supervision. Patients can
remain in severe stages of AD for several years. Error: Reference source not found, 12, Error: Reference
source not found
These drugs are similar yet have distinct pharmacology profiles such as onset of action,
side effect profile, potential drug interactions, ease of administration (e.g. twice a day
versus three times a day), and route of metabolism. However, the clinically relevance of
these differences are unclear and the significance of these differences awaits head-tohead trials.Error: Reference source not found,Error: Reference source not found
This class of drugs is indicated for mild to moderate AD. However, no published results
are available for severe dementia, though open-label follow up from trials suggests that
these drugs continue working as the cholinergic deficit increases.Error: Reference source
not found
Benefits reported for these medications tend to occur at higher doses. However, the
higher the dose, the more likely the side effects.Error: Reference source not found
6.11-12
Given the increase in AD prevalence, more studies are needed to determine the role of
cholinergic medicines in patients with severe AD and to provide comparative data on
therapeutic options for this subset of patients.20
Cochrane reviews of the cholinesterase inhibitors suggest that treatment effects have been
demonstrated with several agents, and that this class is generally more efficacious than
placebo. See also Background Chapter 5. Positive changes in cognition, behavior and
function were demonstrated, however, the disease continues to progress and the treatment
effect is modest and short lived.Error: Reference source not found
Reviewers conclusions for donepezil: In selected patients with mild or moderate Alzheimer
disease treated for periods of 12, 24 and 52 weeks, donepezil produced modest
improvements in cognitive function. No improvements were present on patient selfassessed quality of life and data on many important outcomes are not available.
Furthermore, the 10mg dose showed only a marginal benefit to the 5mg dose. The
practical importance of these changes to patients and caregivers is unclear.21
Reviewers conclusions for galantamine: Patients in these trials were similar to those seen in
earlier anti dementia AD trials, and consisted predominantly of mildly to moderately
impaired outpatients with AD. Evidence from studies show that there was an overall
positive effect for trials of 3, 5 and 6 months in duration. Furthermore, there was
evidence for efficacy of galantamine on global ratings, cognitive tests, assessments of
ADLs (activities of daily living) and behaviour. Reviewers stated that the magnitude of
cognitive effect was similar to other cholinesterase inhibitors including donepezil,
rivastigmine, and tacrine. Also, galantamine's safety profile is similar to that of other
cholinesterase inhibitors with regard to cholinergically mediated gastrointestinal
symptoms. Longer-term use of galantamine has not been assessed in a RCTs
(randomized controlled trials) and is desirable. 22
Reviewers conclusions for Rivastigmine: Studies show that rivastigmine is beneficial for
people with mild to moderate AD. In comparisons with placebo, improvements were
seen in cognitive function, ADL, and severity of dementia with daily doses of 6 to 12 mg.
Further research is needed on dosage (frequency and quantity) in a search for ways to
minimize adverse effects. Moreover, RCTs greater than 26 weeks are needed to
determine the efficacy of rivastigmine. 23
The cholinesterase inhibitors (donepezil and rivastigime) may not be cost effective for the
management of AD 24 but the study that reached this conclusion has been challenged by the
industry which has asserted that it was under powered. Results of this study were asserted
to " incompatible with many drug company-sponsored observational studies and
advertisements claiming remarkable effects of cholinesterase inhibitors" .Error: Reference
source not found In addition, previous claims that donepezil can stabilize cognitive
deterioration and delay nursing home placement by two to three years have not been
validated by this study. The study also showed that the long-term use of donepezil cost the
UK National Health Service more than placebo.Error: Reference source not found The more
general understanding is that these drugs do not work in the more severe states of the
disease.
6.11-13
Anxiety
Apathy
Disturbed effect/mood
Altered ideation/perception
Agent
Antipsychotics,anticonvulsants, antidepressants,
anxiolytics
Antidepressants, anxiolytics, anticonvulsants
Antidepressants, stimulants
Antidepressants, anticonvulsants
Antispsychotics
Vegetative features
There is sufficient evidence from randomized controlled trials to support the use of both
traditional and atypical antipsychotics for the management of agitation and psychosis in
dementia. Of the two classes atypical antipsychotics appear to be better tolerated
compared to traditional antipsychotics.Error: Reference source not found, Error: Reference source not
found
There is evidence that SSRIs (selective serotonin reuptake inhibitors) antidepressants may
be administered and are better tolerated than other antidepressants.
5. Major Problem and Challenges for Disease Control: Why Does the
Disease Burden Persist?
A cure for AD is still not available and clinicians and caregivers are challenged with caring
for an increasing aging population affected by dementia. Increased life expectancy has seen a
rise in chronic medical disease and associated illnesses, including dementia. For example,
there will be an estimated 400% increase in population of North Americans aged 85 and
older by 2050, 40% of whom will develop dementia. Error: Reference source not found
Clinicians providing care for patients with dementia are confronted with numerous
challenges in managing AD. Some of which include employing unique social and
environmental interventions; knowledge and use of increasingly sophisticated medications,
and providing individualized therapy to patients, working with care givers or varying
systems providing care. The burden for the general practitioner is not necessarily an increase
in sophisticated medicines - it is really the lack of specific medicines for AD that is the
problem - the physician has a limited range of therapeutic options, e.g. frequently used
neuroleptics have mixed pharmacologies that can cause memory impairment, etc.
Management of AD is also complex since it requires differentiating and managing various
changing neuropsychiatric and behavioural problems. A balance also has to be reached
between aggressive intervention and palliative care continued treatment versus withdrawal
of medicines, and patient benefit versus caregiver burden. Managing AD is complex and
presents a major public health concern for the today and the future.Error: Reference source
not found,Error: Reference source not found
Risk Factors
The following are some of the risk factors that are thought to have some relationship on the
development of AD. Many of these risk factors are still being studied.
High life expectancy. Normal aging process increases the risk of AD.
Studies indicate that AD may be inheritable. Relatives with AD (i.e. parent or
sibling) are at a risk for developing AD.
Recent research has identified the presenilin 1 gene on chromosome 14 and
the presenilin 2 gene on chromosome 1. Both genes appear to be strong
indicators for Alzheimer Disease at an early age of onset (before the age of
65). Error: Reference source not found
Preliminary research has also found markers on chromosomes 9, 10 and 12
that might be linked to late-onset Alzheimer Disease (over the age of 65).
Several research studies are underway collecting blood samples from people
with Alzheimer Disease and their family members. These samples enable
scientists to analyze DNA material within families with the intent of
identifying genes that may be responsible for causing Alzheimer
Disease.Error: Reference source not found
6.11-17
Risk factor
Down
Syndrome
Head injury
Education
Aluminum
Estrogen
Social,
productive
and
Physical
activity
Comorbid
diseases
Almost all individuals with Down syndrome over the age of 40 have changes to
brain cells characteristic of Alzheimer Disease. In these individuals, dementia
usually develops in 50's or 60's of age.
Some studies have shown that people who have had a head injury with loss of
consciousness have an increased chance of developing Alzheimer disease.
Research into the development of AD as a result of head injuries is
ongoing.Error: Reference source not found The increased risk is probably due to
the upregulation of APP seen after brain trauma.
Several studies have shown that people who have less than six years of formal
education appear to have a higher risk of developing AD. Low education may
reflect early experiences that were not beneficial to brain development. Higher
education is thought to delay the onset of symptoms of Alzheimer Disease
probably due to greater brain reserve or educational activities that may stimulate
brain activity. Education as a protective factor requires more study to determine
whether it is education that makes a difference or other factors related to it (e.g.,
income level).Error: Reference source not found,Error: Reference source not found
The correlation between AD and aluminum is still under debate in the scientific
community. Some studies have indicated that exposure to aluminum in drinking
water may increase the chances of individuals developing Alzheimer
Disease.Error: Reference source not found
Research has been conducted on estrogen and its impact on various diseases,
including AD. Current research indicates that combined estrogen therapy
(estrogen plus progestin) in women over the age of 65 doubled their risk of
developing Alzheimer Disease and Vascular Dementia, over a five-year period.
Research continues to investigate the effects of estrogen-only therapy on
cognition. Previous research has shown that women with Alzheimer Disease
who were treated with estrogen showed no sign of improvement. Error:
Reference source not found,Error: Reference source not found
Recent data from the CSHA-2 (Canada Study for Health and Aging) show that
regular physical activity was associated with reduced risk of AD. This
information supports previous clinical trials showing exercise to benefit
cognitive function. Identifying the protective effect of regular physical activity is
an important finding since it may represent a relatively safe and available
strategy to help prevent AD, as well as many other chronic conditions. The
CSHA-2 recommends that further research still needs to be conducted in this
area.Error: Reference source not found
Hypertension, high cholesterol, diabetes mellitus and low estrogen may affect
the development of AD. Co-morbid diseases that may affect the development of
AD are being researched.Error: Reference source not found ,Error: Reference source not
found,Error: Reference source not found
Other risk
factors
being
studied
6.11-18
Vaccine. Efforts to develop a vaccine so that an immune mediated response targets the
disease are still being investigated. The phase II trial of an active vaccination
approach in AD was stopped in 2001 since it resulted in meningoencephalitis
(inflammation of the brain and surrounding areas). Despite this set back, research
still continues in the area of safe vaccine development, which may be able to
combat AD.Error: Reference source not found The use of passive immunization is
less likely to cause the inflammation seen with the active vaccination approach.
Statins. High cholesterol, an increased risk factor for AD, has also been implicated in the
pathology of AD and is thought to promote amyloid production. New focus on
8th international conference on AD reports that an autopsy study in the US found
that a 10% increase in blood cholesterol level doubles the risk of amyloid
deposits in the brain. Clinical trials in the US to compare the progression of AD in
those taking statins versus placebo are to be launched.Error: Reference source not
found
Neurotransmitter targets. Cholinesterase inhibitors, are currently the only widely approved
class for the treatment of AD. This therapeutic class inhibits the enzyme acetylcholinesterase,
which breaks down acetylcholine in the synaptic cleft and therefore they increase
acetylcholine levels in the brain. These drugs, do not attack the underlying disease pathology,
instead they compensate for the loss of neurons that communicate via this enzyme.
Cholinesterase inhibitors appear to slow down cognitive decline, however the improvements
are very modest. Memantine, which works to inhibit the action of neurotransmitter
glutamate, has been launched in the US and some European countries. It has been approved
for moderate to severe patients Experts within the field suggest that the two classes may be
used in combination or combined with other therapies under development.Error: Reference
source not found, 31
NSAIDS: One such prevention study is evaluating the use of NSAIDS (non steroidal antiinflammatory drugs) on AD. Preliminary results are promising, however AD researchers are
reluctant to recommend NSAIDS given the toxicities (gastrointestinal ulcers, renal toxicity,
hypertension) associated with taking these medicines. Researched are waiting for results
from large RCTs in order to weigh the risks versus benefits of NSAID therapy before making
any recommendations.Error: Reference source not found
Antioxidants. Pathological data indicates that oxidative stress and the accumulation of free
radicals results in neuronal damage in AD. There are several studies evaluating the effects of
antioxidative compounds on AD. Vitamin E and selegeline appear to delay progression.
Research continues on the use of antioxidative vitamins and large US studies are underway
6.11-20
Hormones. The attention and potential uses of hormone replacement therapy to treat AD
is derived from epidemiological, clinical, and neuropathological observations and are still
ongoing. Women are at a higher risk of developing AD than men since women are estrogen
deficient post menopause whereas men benefit from estrogen as testosterone undergoes
aromatization to estradiol. Estrogen is considered to have numerous beneficial properties
some of which were thought to be antioxidant and anti-inflammatory properties,
interactions with neurotransmitters such as acetylcholine and its ability to alter
apolipoprotein which could lower the risk of developing AD. Unfortunately, no studies to
date have demonstrated a positive impact on improving the biological course of AD. Studies
are still ongoing and need to assess the type of HRT administered, timing of HRT in AD,
effect of HRT with cholinergics. Currently, there is insufficient evidence for HRT in AD
management.Error: Reference source not found,Error: Reference source not found
Other Agents. Various other pharmacological agents to treat AD are being studied. Gingko
Biloba, a plant extract that contains numerous pharmacological properties, some of which are
thought to be antioxidative, anti-inflammatory or neurotransmitter modulators. Current
research suggests that the use of Gingko Biloba provides smaller effects that that of
cholinergics. Also, it is currently unknown which of the active components of this alternative
compound contributes to cognitive enhancing effects. Furthermore, the compound is a nonregulated supplement in several countries and standardized preparations are not
available.Error: Reference source not found
Table 7: Current and Some Potential Treatments for ADError: Reference source not
found
Symptomatic
Probable-in
use
Possible-in
clinical trial
Acetylcholinesterase
inhibitors
Donepezil
Rivastigmine
Galantamine
Muscarinic agonists
Inverse
Benzodiazepine
agonists
Transmitter releasing
factors/channel
Disease modification
Vitamin E
Acetylcholinesterase inhibitors
(?)
Memantine (?)
Ginkgo biloba (?)
Antioxidants
Estrogen
NSAIDS
Nootropics e.g. piracetam
NGF stimulators
Amyloid modifying drugs and
6.11-21
Cure
None
Nonevaccination
approaches are
in trial as are
the gamma
secretase
inhibitors
Possible-in
clinical
development
Nicotinic agonists
5HT6 antagonists
PDEIV inhibitors
Gene product
manipulation
Apan-1, APAN
Breaker peptide
CPI-1189
DP 543
MEM 1003
MKC 2313
MPC 7869
Namenda
Nerve growth
factor (gene
therapy)
NS 2330
Phenserine tartate
SR 57667
Indication
Company
Development
Status
Alzheimer disease
GlaxoSmithKline
Phase 1
Alzheimer disease
Alzheimer disease
GlaxoSmithKline
Bristol-Myers Squibb
Phase II
Phase III
Alzheimer disease
Alzheimer disease,
mild cognitive
impairment
Alzheimer disease
Alzheimer disease
Alzheimer disease
Alzheimer disease
Alzheimer disease,
mild cognitive
impairment, vascular
dementia
Alzheimer disease
Alzheimer disease
Alzheimer disease,
neuropathic pain
Alzheimer disease
Neurochem
Cortex Pharmaceuticals
Phase III
Phase II
Praecis Pharmaceutical
Serono
Centaur Pharmaceutcals
Bristol-Myers Squibb
Memory Pharmaceuticals
Phase I
Phase I
Phase II
Phase II
Phase I
Mitsubishi Pharma
Mzriad Genetics
Forest Laboratories
Phase II
Phase II
Phase III
Ceregene
Phase I
Alzheimer disease,
Parkinson disease
Alzheimer disease
Alzheimer disease,
Parkinsons disease
Boehringer-Ingelheim
Pharmaceuticals
Axonyx
Sanofi-Synthelabo
Phase II
6.11-22
Phase II/III
Phase II
Alzheimer disease,
antimitotic
neuropathies (AIM),
multiple sclerosis
Sanofi-Synthelabo
6.11-23
Phase II
Alzheimer disease is an important topic of the key action on "The aging population and
disabilities" of the European Union's Fifth Framework Programme. The European
commission recognizes the impact of AD on individuals and society and the urgent need for
treatments that can prevent, arrest and reverse degeneration and death of neurons. The
multidisciplinary projects launched with EU support set a prerequisite in the understanding
of the fundamental molecular and cellular mechanisms of AD and the development of
diagnostic tools that may identify patients at an early pre-symptomatic stage. Furthermore a
consortium of 21 of the most experienced AD laboratories from Europe and beyond are to
carry our research projects integrating data from studies with tissue cultures and genetically
modified animals into a clinical investigations of demented patients. A broad array of biotechnological methods is also to be used. Results of these studies will lead to diagnostic
screening strategies combing genetic, pathophysiological and biomarker information. Annex
6.11.2 is the records of the current fifth framework research projects related to AD. 36
Six EU-funded projects were launched in 2000 with a total EU support of 2 million over 3
years. The ultimate aim of the projects is to diagnose, prevent, delay the onset or treat
Alzheimer disease.37
6.11-25
Cholinergic therapies only bring about a temporary relief in AD symptoms, and it is not
possible to predict who will respond. It is also unclear whether patients who do not
respond to one anticholinesterase inhibitor will respond to another. Systematic clinical
research is needed to answer these clinical questions. Furthermore, ways of measuring,
determining response, and assessing when medications need to be stopped remain
unclear and need to be addressed.38
There may also be a need for more comparative clinical trials of these agents to determine
which agent offers the greatest benefit and causes least resistance. The effective and
appropriate administration of cholinergic and other medicines requires good baseline
assessment with validated scales for objective measurement. Further work is required
and practice guidelines are needed to assist clinicians in effectively diagnosing patients
suspected with AD. There is also a need for better scales for the non-cognitive
symptoms.Error: Reference source not found,Error: Reference source not found
Cholinesterase inhibitors are licensed for use in mild to moderate AD and at present,
there is insufficient data on their safety and efficacy in severe AD. Further studies are
required to assess this.Error: Reference source not found,Error: Reference source not found
More comparative trials evaluating multiple cholinergic medicines, as well as
combination therapy with different classes for drugs, also remains unanswered and welldesigned RCTs, with clear indications for appropriate doses for various stages of AD are
needed.Error: Reference source not found
Additional well-designed studies, adequately powered, are needed to assess the
beneficial properties of anti-inflammatory compounds such as ginkgo biloba, ibuprofen,
and cerebrolysin.Error: Reference source not found
Studies are also needed to compare and assess different formulations and doses of
vitamin E in altering the course of AD.Error: Reference source not found
Research recommendations for management of non-cognitive behavioural disturbances:
There is a need for more randomized clinical trials on the pharmacological treatment of
anxiety, disinhibition, compulsive behaviors, wandering, agitation, and sleep
disturbances associated with AD. Studies are required to assess which behavioural
disturbance are best treated with pharmacological and non-pharmacological therapies.
Furthermore, comparative studies are needed comparing anxiolytic, tri-cyclic
antidepressants, SSRIs and novel antipsychotic medicines in AD.Error: Reference source
not found
AD is a complex disease overlaid with neuro-psychotic and behavioural symptoms, and
management rarely responds to medicines alone. Important factors other than cognitive
functions and activities of daily living need to be studied. Behavioural modification and
education combined with drug therapies as well as caregivers interventions require
systematic clinical research. This will include time to institutionalization, quality of life
6.11-26
Gaps Between Current Research and Potential Research Issues that Could Make a
Difference
A review of currently available treatments suggests a number of areas for further study.
Some of these recommendations are within the realm of improved evaluation and
assessment.39
Improved detection and evaluation of dementia, especially in the prodromal and early
stages, when treatment that slows progression would be more likely to be beneficial.
This implies the development of a reliable diagnostic tool.
There is a clear need for increase biomarkers for measuring disease progression the lack
of these means that trials of disease modifying therapies will not move ahead as rapidly
as possible. The use of surrogate endpoints e.g. imaging also needs more investigation.
(see below).
Development of consensus on clinically meaningful outcome measures and hard
endpoints, such as institutionalization and mortality.Error: Reference source not found
Within the field of pharmacologic therapy, there is a critical need for medicines with
greater ability to improve cognition or at least halt the progression of dementia. Areas
that are already being actively studied in patients with AD include cholinergic agonists,
vitamin E, NSAIDs and antioxidants.Error: Reference source not found
Despite the progression in the areas mentioned above, research and development needs
to further identify and test new cognition-enhancing medicines based on the
pathophysiology and information learned about the disease from neuroscience and
molecular genetics. For example, pharmacologic agents that prevent or slow amyloid
deposition or remove precipitated amyloid which might serve to prevent or reverse
AD.Error: Reference source not found
Other research directions that can greatly affect management of AD, is the optimal
pharmacologic treatment of noncognitive symptoms, including psychosis, agitation,
depressions and sleep disturbances. Many current recommendations are based on smalluncontrolled studies or agents no longer in common use and/or at doses well above
those used in current practice. There is, therefore, a critical need for randomized
controlled studies and guidelines on up-to-date treatments for non-cognitive symptoms
present in AD.Error: Reference source not found
Clinical questions that need to be further evaluated and studied include what to treat?
There is a problem surrounding the terminology, and diagnosis associated with
dementia and AD. Confusion remains about when to initiate treatment; how to treat -i.e.
what agents to start, how to switch drugs in the case of decreased efficacy, intolerance,
adverse effects or drug interactions and how long to treat AD.Error: Reference source not
found
In addition to symptomatic or palliative options, increased knowledge of the anatomical,
cellular and molecular basis of AD, together with the identification of new drug targets,
which may prevent, slow or delay its onset are needed. These possibilities may be
expedited by the further progress in research and development of improved animal;
introduction of more efficient and effective clinical trials, and the use of non-invasive
6.11-27
imaging to monitor the progression of the disease. It has been estimated that delaying
the onset of AD by approximately 5 years would reduce the numbers dramatically by
about 50% by 2050.40
Combination therapies are likely to offer maximum benefit in longer term disease
modification. See Background Chapter 7.1
trials but are not suitable for short-term duration, proof of-concept trials. There is
also a need to develop an infrastructure to speed up validation studies, such as
large-scale biologic sample collection from ongoing aging populations. The
availability and development of specific imaging technology such as Positron
Emission Tomography (PET) to determine whether changes in the brain or its
function can be identified before the person develops symptoms of the disease is
also needed. Error: Reference source not found
Barriers in academia41. Academic drug discovery and development programs
are usually under funded and lack infrastructure, in terms of staff and equipment
especially at the preclinical level. Furthermore, the lack of communication,
interaction and collaboration between necessary research groups can limit drug
discovery and research. Today, science and medicine requires an interdisciplinary
approach to solving medical conditions.
Barriers in biotechnology 42 AD drug discovery and development is
considered high risk and attracting capital for early high-risk projects is very
difficult, especially when the return on investment is questionable or long-term.
The cost of conducting clinical trials is also another major barrier to small
companies: risks are high and the probabilities of scientific success low. Therefore,
external funding is important. EUROPA, the European commission group to
improve innovation proposes that a small business innovation research
programme (SBIR) mechanism-like that employed in public funding in the US, be
introduced into the FP6-through integrated projects. This will speed up the
creation of new companies and provide capital for small-to-medium sized
enterprises. In the US SBIR mechanisms amounts to US 1.3 billion dollars. 43
Regulatory barriers. Another barrier that affects both the pharmaceutical and
biotech industry is the lack of international harmonization of clinical trials and
regulatory requirements. Designing trials that meet individual requirements is
costly and timely. A further barrier to drug development is the definition of
therapeutic effectiveness of AD medicines. The FDA requires that medicines show
superiority to placebo on a performance-based test and a measure of global
clinical function. Outcome measures are still unspecific and need to be established
by the medical community. Other outcome efficacy measures that affect AD
function are needed to guide drug development, and registration.
11. Conclusion
AD is the most common cause of dementia in people aged > 65 and affects more than 18
people worldwide. This number will increase considerably in the future and will present
enormous financial burdens to health care systems. Thus, there is an urgent need for effective
medicines. Currently only symptomatic treatment is available. While there is research and
development already in this area, much work still is required. This includes: basic research in
the pathophysiology of the disease and its risk factors; noninvasive and clinically effective
diagnostics tools; wider scale outcome efficacy measures for the disease function and
progress and developing medicines that slow progression, halt, or prevent AD from
occurring. Additionally, challenges for clinical services include early diagnosis, and
intervening early with the most appropriate and effective medicine. Error: Reference source
not found
There are several barriers to closing the obvious pharmaceutical "gaps" with regard to AD.
Specific recommendations include the following:
The EU and EU-based philanthropic organizations need to recognize and help overcome the
various scientific and systemic barriers to improving pharmaceutical R&D for Alzheimer
disease and provide funding for making animal models more accessible and affordable. Also
new grant agreements should be implemented that compensate investigators and institutions
while making the models more widely available. There is a need for improved AD
assessment tools, with increased sensitivity and efficiency for patient evaluation for AD
primary prevention. More specifically, curtailing time requirements for clinical staff, data
monitoring and data entry could decrease costs for trials.
6.11-30
6.11-31
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