Creating A New Clinical Assessment Tool forTrials in Early Alzheimer’s DiseaseVeronika Logovinsky, MD, PhDEisai Inc.      ...
Background and Objectives•   Convergent efforts within Alzheimer’s disease (AD) field to treat    early stages of disease•...
Development of New Composite Measure at Eisai• Assumptions  – Certain items in existing clinical scales are sensitive for ...
Final Composite:       Items and Their Relative Contributions                                                             ...
New Composite Has Been Extensively Tested andValidated with Retrospective Data• Split sample validation and reliability• R...
New Composite Improves Responsiveness/Sample Size                      Required Compared to Original Scales               ...
Responsiveness to Treatment Effect: Difference of Donepezil   Versus Placebo in Change from Baseline                      ...
Summary• Improved sensitivity to decline• Allows for substantially smaller sample sizes• Responsive to current treatments•...
Thanks!Eisai Inc.•   Andrew Satlin•   Jinping Wang•   Carlos Perdomo•   Shobha Dhadda•   Ira Do•   Martin RabePentara• Suz...
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Logovinsky Alzforum Feb 28 2013 final

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  • Composite score is a weighted sum of items using their PLS coefficients as the weights Addition of ADL or NTB items did not improve sensitivity of the combination
  • CDR (vs. ADAS-Cog) tracks well with disease progression; Further improvement possible for MCI using enriched populations, such as ApoE ε4 carriers (reduced heterogeneity and increased progression)
  • CDR-SB items may not be as reversible, therefore do not change due to treatment.
  • Logovinsky Alzforum Feb 28 2013 final

    1. 1. Creating A New Clinical Assessment Tool forTrials in Early Alzheimer’s DiseaseVeronika Logovinsky, MD, PhDEisai Inc. © 2012 Eisai Inc.
    2. 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 2 Eisai Confidential
    3. 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 3 Eisai Confidential
    4. 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% 4 Eisai Confidential
    5. 5. New Composite Has Been Extensively Tested andValidated 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 5 Eisai Confidential
    6. 6. New Composite Improves Responsiveness/Sample Size Required Compared to Original Scales 7000 5000 Pooled 2000 MCI 6000 APOε4 CarrierSample 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. 7. Responsiveness to Treatment Effect: Difference of Donepezil Versus Placebo in Change from Baseline Study ADAS- Population Treatment† CDR-SB MMSE ADCOMSStudy duration CogEisai donepezil MCI 12 mo 10 mg - - - -Study 1Eisai donepezil 5 mg + - + + Mild AD 6 moStudy 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 7 Eisai Confidential
    8. 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 studiesEisai recently initiated large Phase 2 study with BAN2401 (monoclonalantibody directed against protofibrils)New composite is used as clinical outcome assessment in the study 8 Eisai Confidential
    9. 9. Thanks!Eisai Inc.• Andrew Satlin• Jinping Wang• Carlos Perdomo• Shobha Dhadda• Ira Do• Martin RabePentara• Suzanne B. Hendrix• Stephanie Stanworth 9 Eisai Confidential

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