Transcript Alzheimer - WHO archives

Stroke and Alzheimer’s
Disease
Dr Jackie Hunter
Senior Vice-President
Neurology & Gastrointestinal
Centre of Excellence for Drug
Discovery
GSK
Harlow
Outline of Talk
• General Comments on Process
• Stroke (chapter written by Eduardo Sabate &
Sunil Wimalaratna)
• Alzheimer’s Disease (chapter written by Saloni
Tanna)
The Burden of Stroke
• 1M new strokes p.a. in
Europe
• 200,000 deaths p.a. in
Europe
• Estimate of 1.9 million
strokes by 2008 (US,
Europe, Japan)
• Major cause of disability
with 1/4 to 1/2 victims
requiring dependence
Stroke: Pathophysiology
80%
20%
Issues 1: Current Management
• Intervention
 Thrombolysis only possible within 3 hours and when
haemorrhagic stroke ruled out by scan
 Many centres unable to screen patients within the
therapeutic window
 Most patients don’t present within 3hrs
 Previous trials of neuroprotectants have been
spectacularly unsuccessful
• Supportive care
 Specialist stroke centres shown to be of benefit
Issues 2: Lack of New Therapies
Future treatment options divided into:• Reducing delays
• Identification of patients that could respond to
specific treatment options
• Prolonging treatment window
• Late intervention
Initial Perfusion Deficits to
Identify Patients
Patient
A
DWI @ 6 hrs
Patient B
DWI @ 6 hrs
Patient A
Patient A
MTT @ 6 hrs
DWI @ 3 days
Patient B
MTT @ 6 hrs
Patient B
DWI @ 4 days
Options for Future Research
• Prolonging treatment window
 ‘Penumbra’ means there is potentially recoverable
tissue in many patients
 Many mechanisms tried but failure rate high
 Clinical trials expensive and prolonged
• Late intervention
 Potential for regenerative therapies
 But endpoints etc poorly defined
Days
Hours
>50% patients
2
7
8 hrs
Weeks/Months
14
+
Ca Na
Glut Enzymes
Future
Stroke
Therapeutic
strategies
I
N
J
U
R
Y
Necrosis
Apoptosis
Inflammation
Repair
Remodeling
Plasticity
Prevention/Protection
Acute Intervention
Regeneration/Functional Recovery
The Burden of Alzheimer’s
Disease

Leading cause of dementia

Affects 18M people world
wide

The average duration of
disease is 8 years
Direct and indirect costs are
estimated in excess of 100
billion dollars per year



No disease modification
treatment
No specific diagnostic
Pathological Hallmarks of
Alzheimer’s Disease
•Senile plaques – toxic b amyloid fibrils
•Neurofbrillary Tangles
Neurofibrillary tangles
Dystrophic neurites
Ab
Senile plaques
AD and Points of Therapeutic
Intervention
Abnormal APP metabolism
Abnormal phosphorylation
of tau
b amyloid deposition
Neurofibrillary tangles
Fibrilisation
Plaque formation
Cell loss
Inflammation
(cytokines,
free radicals etc)
Neurotransmitter deficits
Glucose
hypometabolism
Issues 1: Diagnosis
• No unequivocal diagnosis for AD, especially in
early stages
 Relationship between MCI and AD
 Differential diagnosis from other dementias
• Important areas highlighted for research
 New imaging agents for amyloid and other diagnostic
biomarkers
 Improved characterisation of non-cognitive
symptoms
Issues 2: Lack of Effective
Therapy
• Current agents only symptomatic
 Cholinesterase inhibitors (mild-moderate)
 Memantine (moderate to severe)
• Not all patients respond- doses limited by side
effects
• Focus is on cognitive effects
• Management of non-cognitive effects not clearcut and may further impair cognition
Issue 3: Lack of basic disease
understanding
• Genetic factors have been identified which have
aided disease understanding
• Some risk factors have been identified
• But lack of basic knowledge means: Few validated targets for either symptomatics or
disease modification
 Animal models essentially pharmacodynamic
 Lack of surrogate markers
Potential Disease Modifying
Approaches
•
•
•
•
•
•
•
b secretase
g secretase
Vaccination
Statins
Antioxidants
NSAIDs
Growth factors
Combination therapies will be important
Other Important Gaps
• Clinical trial design
 Long and costly especially for disease modification
 Need reliable predictors of outcome
 Guidelines for MCI studies
• Encouraging biotech/small pharma to invest in
such trials
Summary
Stroke and AD have many similarities
•
•
•
•
Huge burden which increases with age
Treatment options currently limited
A number of potential treatment options on the horizon
But trials costly and failure rate highbiomarkers/surrogates are critically needed
Ideal diseases for public/private partnership initiatives
BACKUPS
APP processing cascade
soluble
APP
Amyloid Precursor Protein
soluble
APPb
N
4
b
b
2

1
3
b&g
cleavage
b site
 site
g
Soluble Ab (1-40, 1-42)
Ab domain
CELL MEMBRANE
g cleavage site (Presenilin-1?)
C
Neuronal
cell loss
GSK’s Comments On The Report
• Overall a fairly balanced and helpful report.
 Demonstration of dialogue, partnerships and need for
combined efforts
• Consultation with industry has been very good
• Key disease areas identified for focused development and
improved treatment. Broad agreement with
recommendations, in particular stimulating basic research
on areas such as biomarkers
• Recognition that the pharmaceutical industry will play a
key role in addressing areas of unmet need is helpful and
likely to drive partnerships
• Focus on reducing barriers to innovation welcome and
industry will be looking at ways of taking this forward at a
Nhational and European level.