1. Stroke and Alzheimer’s Disease Dr Jackie Hunter Senior Vice-President Neurology & Gastrointestinal Centre of Excellence for Drug Discovery GSK Harlow

2. Outline of Talk General Comments on Process Stroke (chapter written by Eduardo Sabate & Sunil Wimalaratna) Alzheimer’s Disease (chapter written by Saloni Tanna)

3. 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

4. Stroke: Pathophysiology 80% 20%

5. 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

6. 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

7. 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 A DWI @ 6 hrsMTT @ 6 hrs

8. 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

9. Ca Na + Glut Enzymes Hours DaysWeeks/Months >50%patients 8 hrs 7 NecrosisApoptosis Repair Remodeling Plasticity I N J U R Y 14 2 Inflammation Prevention/Protection Acute Intervention Regeneration/Functional Recovery Future Stroke Therapeutic strategies

10. l Leading cause of dementia l Affects 18M people world wide l The average duration of disease is 8 years l Direct and indirect costs are estimated in excess of 100 billion dollars per year l No disease modification treatment l No specific diagnostic The Burden of Alzheimer’s Disease

11. Pathological Hallmarks of Alzheimer’s Disease Senile plaques – toxic  amyloid fibrils Neurofbrillary Tangles Neurofibrillary tanglesDystrophic neurites AA Senile plaques

12. AD and Points of Therapeutic Intervention Abnormal APP metabolism  amyloid deposition Fibrilisation Plaque formation Abnormal phosphorylation of tau Neurofibrillary tangles Cell loss Inflammation (cytokines, free radicals etc) Glucose hypometabolism Neurotransmitter deficits

13. 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

14. 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

15. 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

16. Potential Disease Modifying Approaches  secretase  secretase Vaccination Statins Antioxidants NSAIDs Growth factors Combination therapies will be important

17. 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

18. 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

19. BACKUPS

20. Neuronal cell 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 2 3 4

21. 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.