stroke and alzheimer’s disease dr jackie hunter senior vice-president neurology &...
TRANSCRIPT
Stroke and Alzheimer’sDisease
Dr Jackie Hunter
Senior Vice-PresidentNeurology & GastrointestinalCentre of Excellence for Drug DiscoveryGSKHarlow
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
DWI @ 3 days
Patient A
MTT @ 6 hrs
Patient B
DWI @ 6 hrs
Patient B
DWI @ 4 days
Patient B
Patient APatient A
DWI @ 6 hrs MTT @ 6 hrs
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
Ca Na+
Glut Enzymes
Hours Days Weeks/Months>50% patients
8 hrs 7
Necrosis Apoptosis
RepairRemodeling
Plasticity
I
N
J
U
R
Y
142
Inflammation
Prevention/Protection Acute Intervention Regeneration/Functional Recovery
Future StrokeTherapeutic strategies
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
The Burden of Alzheimer’s Disease
Pathological Hallmarks of Alzheimer’s Disease
•Senile plaques – toxic amyloid fibrils•Neurofbrillary Tangles
Neurofibrillary tangles Dystrophic neurites
A
Senile plaques
AD and Points of Therapeutic Intervention
Abnormal APP metabolism
amyloid deposition
Fibrilisation
Plaque formation
Abnormal phosphorylationof tau
Neurofibrillary tangles
Cell loss
Inflammation(cytokines, free radicals etc)
Glucose hypometabolism
Neurotransmitter deficits
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 clear-
cut 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
• secretase• 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 high-
biomarkers/surrogates are critically needed
Ideal diseases for public/private partnership initiatives
BACKUPS
Neuronalcell loss
Aggregation
& cleavage
Soluble A (1-40, 1-42)
site
site
soluble APP
soluble APP
CELL MEMBRANE
cleavage site (Presenilin-1?)
Amyloid Precursor Protein
A domain
APP processing cascade
C
N
1
23
4
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.