1. FOCUSED. TRUSTED. GLOBAL.EXPERTSDrug Development in Alzheimers Disease Challenges and Opportunities Samer E. Kaba, M.D. Medical Director Neuroscience Clinical Assistant Professor of NeurologyEmory University

2. FOCUSED. TRUSTED. GLOBAL. Pathology o AD is a degenerative disease characterized by: Loss of neurons Intracellular accumulation of neurofibrillary tangles Accumulation of amyloid plaques Brain and hippocampal atrophy o Genetic factors have a definitive role Multiple genes identified o The pathological changes are similar to normal aging qualitatively, but different quantitatively 3. FOCUSED. TRUSTED. GLOBAL. Microscopic Changes in AD 4. FOCUSED. TRUSTED. GLOBAL. Macroscopic Changes in AD 5. FOCUSED. TRUSTED. GLOBAL. Pathophysiology o Protein Abnormalities in Alzheimers Disease -Amyloid Tau o Synapse Related Abnormalities Synaptic Failure Depletion of Neurotrophin and Neurotransmitters o Mitochondrial Dysfunction Oxidative Stress Insulin-Signaling Pathway Vascular Effects Inflammation 6. FOCUSED. TRUSTED. GLOBAL. Clinical Presentation o Cognitive decline Short- term memory impairment Confusion Decreased visuo-spacial orientation Reduced comprehension and other verbal skills o Behavioral changes Personality and mood changes Sleep disturbance Agitation Paranoia and hallucinations Loco-motor slowing 7. FOCUSED. TRUSTED. GLOBAL. Therapeutic Targets o Symptomatic treatments Mostly neurotransmitters based Existing therapies are all symptomatic Can work in different stages of the disease o Disease modifying therapies None is available to date, the race is on! To target the changes leading to progressive tissue damage and clinical manifestations Early treatment is crucial 8. FOCUSED. TRUSTED. GLOBAL. Symptomatic Therapies o Cognitive enhancement Cholinesterase inhibitors: Cognex Aricept, Excelon, Razadyne (formerly Reminyl) NMDA Agonists Namenda o Behavioral modification Antipsychotic drugs Antidepressant Hypnotics 9. FOCUSED. TRUSTED. GLOBAL. Current Outcome Measures in AD Trials: o Primary outcomes Cognition -ADAS-cog Global - CIBIC+ o Secondary Outcomes Behavioral NPI or BEHAVE-AD ADL DAD or ADCS-ADL o Caregiver burden Direct relationship to institutionalization of patient o Pharmaco-economics Complex but of increasing interest to governments and third party payers 10. FOCUSED. TRUSTED. GLOBAL. Challenges in DM therapies 11. FOCUSED. TRUSTED. GLOBAL. Disease Modifying Therapy o No disease modifying therapy for AD is available yet o Slow progress because: Difficulty in identifying therapeutic targets Sub-optimal collaboration with academia The lack of adequate animal models of AD The limitations of standard clinical endpoints (ADAS- Cog, MMSI, etc.) The need for biomarkers of disease activity and tissue injury Tactical challenges to AD trials 12. FOCUSED. TRUSTED. GLOBAL. Biomarkers of AD A Critical Need o Providing surrogate measures for evaluating compounds in early development (go-no-go decisions) o Confirming the eligibility of patients for trials o Selecting homogeneous groups of patients o Providing more objective endpoints for confirmatory trials o Confirming the clinical findings of confirmatory controlled trials o Illustrating a positive effect on tissue injury and disease progression 13. FOCUSED. TRUSTED. GLOBAL. Biomarkers of AD Modalities o Brain imaging MRI: Volumetric MRI Functional MRI, Nuclear: FDG-PET Amyloid imaging (PiB) o Biological testing Tau and P-tau protein in CSF Amyloid A4 in CSF o Electrophysiology Quantitative EEG (Brain Mapping) Long latency evoked potentials 14. FOCUSED. TRUSTED. GLOBAL. Brain Mapping 15. FOCUSED. TRUSTED. GLOBAL. Volumetric Measurement of Hippocampal Atrophy 16. FOCUSED. TRUSTED. GLOBAL. Functional MRI 17. FOCUSED. TRUSTED. GLOBAL. PET Scan in AD 18. FOCUSED. TRUSTED. GLOBAL. Outcome Measures o Cognitive Measures ADAS-Cog (Alzheimer Disease Assessment Scale Cognitivesubscale) MMSE (Mini Mental State Examination) o Functional Rating Scales ADCS-ADL (Alzheimer Disease Cooperative Study Activities ofDaily Living) o Global ratings of severity and change CIBIC/CIBIS (Clinician Interview-based Impression of Change) CDR (Clinical Dementia Rating) 19. FOCUSED. TRUSTED. GLOBAL. ADAS-Cog Limitations o Ceiling and floor effects o Non-linear sensitivity More sensitive in moderate disease o Inter-rater and intra-rater variability Rater training and drift should be considered in trials o Change in scores do not always translate into clinical benefit o Prone to practice effect Should not be administered frequently 20. FOCUSED. TRUSTED. GLOBAL. Tactical Challenges in AD Trialso Early disease: Patients acceptance / motivation The need for long-term follow up Competing trialso Moderate disease Finding treatment nave patients Need for reliable caregiver Co-morbiditieso Advanced Disease Behavioral problems more pronounced Institutionalized patients Co-morbidities Consent issues