1. Biomarker Integration
Opportunities and Challenges of Accelerated
Proof-of-Concept Studies in
Neurodegenerative Diseases
Thierry Sornasse, Ph.D.
Translational Medicine, Biomarker Integration,
Elan Pharmaceuticals, Inc.
10/06/2010

2. Background

3. Accelerated Proof-of-Concept
Diagnosis
Earlier GO / No GO
Disease Stratification Right population
Risk
Targeted Shorter Faster entry to
Smaller Phase 3
Toxicodynamics Phase 2
Pharmacodynamics Sensitive end points Higher chance of
success
Disease Progression
Integrated Biomarker Strategy

4. Biomarker Strategy: parallel development
Discovery Nonclinical Dev. Early Clinical Dev.
Target Candidate IND Phase 2
Drug – Target Interaction: Engagement, Pharmacodynamics & Toxicodynamics
POC in Animal Characterization in Animal
Concepts
Prototype NC Method Defined  Validated NC Method
POC in Human Application
Prototype C Method
Defined C Method Validated C Method
Disease State and Progression
Assumptions Nonclinical Translation
Requirements
Candidate Technical POC in
Gap Analysis Pre-Competitive initiatives Biomarker Feasibility Human
Current assets Internal Clinical Studies

5. Challenges

6. The Neurodegenerative Diseases Challenge
US Population over 65
Aging population
% Population
Increase in the prevalence and incidence of
Alzheimer’s disease and Parkinson’s disease
NO disease modifying therapies
Individuals (1,000)
Major unmet medical need
Potential for a major economical and
societal burden

7. The Alzheimer’s Disease Challenge
A neurodegenerative disease characterized by progressive decline of
memory and other cognitive abilities
2010 2030 2050
~5.3 million patients ~7.7 million patients ~13 million patients
~450,000 new cases ~615,000 new cases ~960,000 new cases
$172 billion/year cost
7th leading cause of death
Cause of death
• AD increased by 46% between 2000 and 2006
• During the same period, stroke, colon cancer, breast
cancer and heart disease decreased

8. Disease Modifying Therapy Challenge
Alzheimer’s Disease Progression Standard clinical end points
• Applicable to clinical stage only
 Not ideal for the development of
disease modifying therapies
• Relatively insensitive
 Long study duration (~ 18 mo.)
 Large cohorts
Improved end points
• Disease state biomarkers
Clinical stage  Identify patients prior to clinical
onset
Disease modifying
Drugs • Disease progression biomarkers
Symptomatic  Higher sensitivity
 Shorter studies – fewer patients

9. Opportunities

10. Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Subjects
• 200 NORMAL 3 yrs
• 400 MCI 3 yrs
• 200 AD 2 yrs
• Visits every 6 months
Standardized procedures
• Clinical, blood, cerebrospinal fluid
• Cognitive Tests
• 1.5T MRI
Special procedures (subset)
• 3.0T MRI (25% sites)
• FDG-PET (50% sites)
• PiB-PET (approx 100)
57 Clinical Sites
Focus on biomarker qualification through standardization
Open access to 6 years of data (2004 – present)

11. ADNI Imaging Biomarkers
Amyloid accumulation
NC MCI AD
Alzheimer’s Disease Progression
[11C] PIB PET
Neuron dysfunction (glucose uptake)
NC AD
Brain atrophy
NC AD
12-months change in cortical thickness

12. Amyloid Accumulation Biomarker
Cerebrospinal fluid Amyloid 42 fragment
Identification: 1995 Characterization: 1998 Qualification: 2010
NC 206 ± 55
N = 100
P < 0.0001
AD
NC 222 ± 60
CSF A 42 (pg/mL)
CSF A 42 (pg/mL)
N=5
163 ± 55 174 ± 59
MCI
N = 195 N = 111
144 ± 37 145 ± 43
N = 37 N = 42
0 1 2
12 12–36
AD NC OND 144 ± 41
N=37 N=20 N=32 N Apo 4 Alleles AD N = 100
Motter et al. Ann. Neurol. 38:643 Galasko et al. Arch. Neurol. 55:937

13. ADNI Biomarkers: impact on POC studies
• Disease state (MCI  AD)
 CSF A 42 & P-Tau levels
 Early AD patient enrichment
 Targeted POC studies
• Disease progression Population size required to detect 25%
change over 12 months with 80% confidence
 Volumetric MRI End Point N
 Greatly enhanced sensitivity ADAS-COG 11 814
 Smaller / faster POC MRI Hippocampal Volume 252
• Expanded disease progression
 Functional imaging (FGD-PET, fMRI)
 Data enrichment
 Informative POC

14. The Parkinson Progression Markers Initiative (PPMI)
Expanding the ADNI model to Parkinson’s disease biomarker research
Subjects (target)
• 200 age- and gender matched healthy controls
• 400 de novo PD subjects
Government agencies • 3 to 5 year follow up
Procedures
PD Foundations • Motor & neuropsychiatric assessment
• MRI & DaTSCAN
• Olfaction
Industry
• Blood, CSF, and DNA collection
19 sites (15 US + 4 EU)
Focus on biomarker discovery and initial qualification
Open access to data

15. Drug – Target Interaction (DTI) Biomarkers
Nonclinical Translation Clinical
Target Off-target
engagement engagement
PK/PD Model
Pharmacology Proximal Proximal
PD TD Context
Toxicology
Connectivity
Distal Distal
DMPK Confounding
PD TD
factors
Activity Toxicity
Positive Negative

16. Summary
Translation Research Open Collaborations
DTI Biomarkers Disease Biomarkers
Accelerated POC
Reduced Development Time
New Drugs
Impact of Neurodegenerative Diseases
Aging Population Standard of Care