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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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

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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

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Microscopic Changes in AD

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Macroscopic Changes in AD

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Pathophysiology
o Protein Abnormalities in Alzheimer's 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

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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

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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

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Symptomatic Therapies
o Cognitive enhancement
 Cholinesterase inhibitors:
• Cognex®
• Aricept®, Excelon®, Razadyne® (formerly Reminyl®)
 NMDA Agonists
• Namenda®
o Behavioral modification
 Antipsychotic drugs
 Antidepressant
 Hypnotics

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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

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Challenges in DM therapies

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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

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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

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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

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Brain Mapping

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Volumetric Measurement of Hippocampal
Atrophy

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Functional MRI

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PET Scan in AD

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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)

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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

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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