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.