Drug development in Alzheimer's Disease


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Presentation outlining new techniques and issues with regard to drug development in Alzheimer's patients, by Dr. Samer Kaba of Medpace.

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Drug development in Alzheimer's Disease

  1. 1. FOCUSED. TRUSTED. GLOBAL.EXPERTS Drug Development in Alzheimer’s Disease Challenges and Opportunities Samer E. Kaba, M.D. Medical Director – Neuroscience Clinical Assistant Professor of Neurology Emory University
  2. 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. 3. FOCUSED. TRUSTED. GLOBAL. Microscopic Changes in AD
  4. 4. FOCUSED. TRUSTED. GLOBAL. Macroscopic Changes in AD
  5. 5. FOCUSED. TRUSTED. GLOBAL. Pathophysiology o Protein Abnormalities in Alzheimers Disease  β-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. 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. 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. 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. 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. 10. FOCUSED. TRUSTED. GLOBAL. Challenges in DM therapies
  11. 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. 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. 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 βA4 in CSF o Electrophysiology  Quantitative EEG (Brain Mapping)  Long latency evoked potentials
  14. 14. FOCUSED. TRUSTED. GLOBAL. Brain Mapping
  15. 15. FOCUSED. TRUSTED. GLOBAL. Volumetric Measurement of Hippocampal Atrophy
  16. 16. FOCUSED. TRUSTED. GLOBAL. Functional MRI
  18. 18. FOCUSED. TRUSTED. GLOBAL. Outcome Measures o Cognitive Measures  ADAS-Cog (Alzheimer Disease Assessment Scale –Cognitive subscale)  MMSE (Mini Mental State Examination) o Functional Rating Scales  ADCS-ADL (Alzheimer Disease Cooperative Study – Activities of Daily Living) o Global ratings of severity and change  CIBIC/CIBIS (Clinician Interview-based Impression of Change)  CDR (Clinical Dementia Rating)
  19. 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. 20. FOCUSED. TRUSTED. GLOBAL. Tactical Challenges in AD Trials o Early disease:  Patients acceptance / motivation  The need for long-term follow up  Competing trials o Moderate disease  Finding treatment naïve patients  Need for reliable caregiver  Co-morbidities o Advanced Disease  Behavioral problems more pronounced  Institutionalized patients  Co-morbidities  Consent issues