1. Creating A New Clinical Assessment Tool for
Trials in Early Alzheimer’s Disease
Veronika Logovinsky, MD, PhD
Eisai Inc.
© 2012 Eisai Inc.

2. Background and Objectives
• Convergent efforts within Alzheimer’s disease (AD) field to treat
early stages of disease
• Disease modification treatments need to be studied in Early AD
populations
• Early AD population: disease continuum from MCI to mild
Alzheimer’s dementia
• Widely recognized by the AD community that no standard
clinical endpoints exist that are sensitive to disease progression
and treatment effect in Early AD
• Significant burden for conducting trials in Early AD (particularly
MCI) → long and large trials, difficult to impossible to manage
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3. Development of New Composite Measure at Eisai
• Assumptions
– Certain items in existing clinical scales are sensitive for early disease stages
– Can develop and optimize new assessment by selecting and combining these
items
• Approach
– Develop a statistical model to analyze placebo data across multiple MCI
studies over 1 year
– Determine most sensitive combination of items from existing clinical tools
(ADAS-Cog, MMSE, CDR-SB, NTB, …)  the new clinical measure
– Assess behavior of the new tool across multiple mild Alzheimer’s dementia
studies
– Assess sensitivity of the new tool to treatment effects in MCI and mild
Alzheimer’s dementia
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4. Final Composite:
Items and Their Relative Contributions
% of
Maximum % of Observed
Composite
Possible Composite Maximum
Observed
Delayed Word Recall 10 4% 10 6% • ADAS-cog items
contribute ~22%
Orientation 8 7% 7 9%
ADAS
(vs. ~17%
Word Recognition 12 2% 12 3% possible)
Word Finding Difficulty 5 4% 4 4% • MMSE items
contribute ~18%
MMSE
Orientation to Time 5 11% 5 15%
(vs. ~13%
Constructional Praxis 1 2% 1 3% possible)
Personal Care 3 8% 1 4% • CDR-sb items
Community Affairs 3 17% 2 15% contribute ~61%
(vs. ~71%
Home and Hobbies 3 14% 2 13% possible)
CDR
Judgment and Problem
3 11% 2 10%
Solving
Memory 3 9% 2 8%
Orientation 3 12% 2 11%
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5. New Composite Has Been Extensively Tested and
Validated with Retrospective Data
• Split sample validation and reliability
• Responsiveness to change with disease progression
– Compare Mean to Standard Deviation Ratio (MSDR) between the composite
and standard scales
• MCI population
• Enriched MCI subgroups (CSF Aβ positive and ApoE4 positive)
• Mild Alzheimer’s dementia patient population combining placebo data from
3 studies
• Responsiveness to treatment effect
– MCI population
– Mild Alzheimer’s dementia
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6. New Composite Improves Responsiveness/Sample Size
Required Compared to Original Scales
7000
5000 Pooled
2000
MCI
6000 APOε4
Carrier
Sample Size per arm
4000 MCI CSF
5000 Aβ(1-42)
Pooled
Mild AD
4000 3000
1000
3000
2000
2000
1000
1000
0 0 0
ADAS-cog Composite MMSE Composite CDR Composite
Score Score Score

7. Responsiveness to Treatment Effect: Difference of Donepezil
Versus Placebo in Change from Baseline
Study ADAS-
Population Treatment† CDR-SB MMSE ADCOMS
Study duration Cog
Eisai donepezil
MCI 12 mo 10 mg - - - -
Study 1
Eisai donepezil 5 mg + - + +
Mild AD 6 mo
Study 3 10 mg + - - +
10 mg - - + +
ADCS MCI 12 mo 2000 IU
- - - -
Vitamin E
+ indicates statistical significance at alpha=0.05; - indicated statistical significance was not reached
† Treatment was donepezil unless otherwise indicated
• Responsiveness to treatment effect is driven by ADAS-Cog and MMSE
• CDR-SB alone is not responsive to treatment effect
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8. Summary
• Improved sensitivity to decline
• Allows for substantially smaller sample sizes
• Responsive to current treatments
• Valid as a clinical outcome
• Can be used as single primary outcome assessment for Early AD studies
Eisai recently initiated large Phase 2 study with BAN2401 (monoclonal
antibody directed against protofibrils)
New composite is used as clinical outcome assessment in the study
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9. Thanks!
Eisai Inc.
• Andrew Satlin
• Jinping Wang
• Carlos Perdomo
• Shobha Dhadda
• Ira Do
• Martin Rabe
Pentara
• Suzanne B. Hendrix
• Stephanie Stanworth
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