Stroke and Alzheimer’s Disease Dr Jackie Hunter

1. Stroke and Alzheimer’sDiseaseDr 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 20% 80%

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. Patient A DWI @ 3 days Patient B Patient B Patient B MTT @ 6 hrs DWI @ 6 hrs DWI @ 4 days Initial Perfusion Deficits to Identify Patients Patient A Patient A DWI @ 6 hrs MTT @ 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. Days Weeks/Months Hours >50% patients 14 2 7 8 hrs + Ca Na Glut Enzymes I Necrosis Apoptosis N J Inflammation U Repair R Remodeling Y Plasticity Future Stroke Therapeutic strategies Prevention/Protection Regeneration/FunctionalRecovery Acute Intervention

10. 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

11. Pathological Hallmarks of Alzheimer’s Disease • Senile plaques – toxic b amyloid fibrils • Neurofbrillary Tangles Neurofibrillary tangles Dystrophic neurites Ab Senile plaques

12. 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) 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 • b secretase • g 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. APP processing cascade soluble APP Amyloid Precursor Protein soluble APP N Neuronal cell loss 4 Aggregation   2 3   &  cleavage  site 1 g Soluble Ab (1-40, 1-42)  site Ab domain CELL MEMBRANE  cleavage site (Presenilin-1?) C

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.