MSD Update for GBSC Face-to-Face (July 14, 2012)
Pankaj Oberoi, Ph.D.
Director, Research and Development
Director, Scientific Services
MSD Confidential and Proprietary
8/17/2012
MSD-S00XXXX
Slide 1
Outline: MSD Update for GBSC
 MSD’s Role in Clinical Biomarker
 MSD Completed ISO Certification; Validated Manufacturing Facility
 Commercially Released Ab42 and Total Tau Assays
 Analytical Validation to be Presented at AAIC
 3 Development Lots
 Matrix-Based Controls Performance Charts
 Clinical Utility of Assays to be Presented at AAIC
 149 samples: Normal, MCI, AD
 Matrix tolerance at recommended dilutions.
 Initiated a Multi-Site Study
 Testing Lab Certification and Proficiency Program
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Slide 2
3
MSD’s Biomarker Mission
RESEARCH
ELISA
5000+ Analytes
Variable Quality
Relative Quantitation
Diverse Species
CLINICAL
BIOMARKERS
TRADITIONAL
CLINICAL
DIAGNOSTICS
Abbott, Roche, Siemens
Humans
Rigorous Quality
5000+ Analytes
Diverse Species
Rigorous Quality
High Throughput
Limited Sample
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8/17/2012
100 Analytes
Single Marker
Absolute Quantitation
Absolute Quantitation
Regulatory Approval
Multi-Analyte
MSD-S00XXXX
Slide 3
MSD is now ISO Certified
4
 ISO 13485
 Medical device standard
 Applied to our product development process
 ISO 9001
 For our manufacturing and operation
 This certification will:
 Help MSD make better products
 Provide a better customer experience
 Enable MSD to submit products for
regulatory approval
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8/17/2012
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Slide 4
New Facilities for Validated Biomarker Kits
5
 Existing Building (100,000 SF)
 13 Acres
 Adjacent to I-270 and Corporate HQ
 Room for Expansion
 Additional buildings can be built on the
land
 New manufacturing site
 Full renovation for purpose built facility
 Funding for renovation already in place
 Occupy mid-2013
 Next to New Corporate
Headquarters
 Adjoining properties
 Total 26 Acres
 Additional 170,000 SF office and labs
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Slide 5
Antibody Characterization and Incoming Raw Materials
Dynamic Light Scattering (DLS)
PAGE
Antibodies
Processed to
Remove Excipients
Characterization of
Aggregation and
Degradation
Non-denaturing Denaturing
25015010075-
2501501007550-
50-
37-
37-
25-
20-
Functional Tests on
Pilot Lots
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8/17/2012
252015-
Capillary Iso-Electric Focusing (cIEF)
1510Sample Lot
Reference Lot
MSD-S00XXXX
Slide 6
Critical Reagent Reproducibility
Monday: P2-036
Lot A
Lot B
Lot C
38
Aggregated
peptide
188
98
62
17
14
- Oligomer
6
- Monomer
3
% Recovery Norm. to Expected
140
120
100
80
60
40
4C
Rm Temp
37C
20
0
0
5
10
15
20
25
30
# of Days at Storage Condition
 Raw material characterization of peptide critical for reproducibility.
 Development of robust diluents to allow for stability of peptide
 Round-robin study to see differences between kit vendor material
MSD Confidential and Proprietary
8/17/2012
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Slide 7
New Validated Kits Release June 2012
MULTI-ARRAY® Kits
Analyte
Catalog #
Human Total Tau
Tau
K151LAE-1, -2, -4
Human Ab42
Beta amyloid (Abeta or Ab) 42
K151LBE-1, -2, -4
Total Tau
Ab42
Kit Size
List Price
Kit Size
List Price
1 Plate
$650
1 Plate
$650
5 Plate
$2,778
5 Plate
$2,954
25 Plate
$11,820
25 Plate
$13,298
 Kits are on-the-shelf; shipping 1-3 days
 Standard lot size 1000 plates, larger lots on request
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Slide 8
Both Kits Went Through Full Analytical Validations
 Built 3 kit lots from independent raw material lots.
Monday: P2-036 and P2-037
 Summary of Validation Data Presented in Product Insert and Posters
 Precision and Accuracy Studies
 Matrix tolerance of Spike and Recovery and Dilution Linearity
 Specificity to the 42 peptide
 Tolerance to interfering peptides
 Effects of blood interference
 Inter-lot reproducibility of well characterized samples.
 Stability of kit components
 Freeze-thaw stability of calibrators, controls, and diluents
 4oC stability of calibrators and detection antibodies
 Real time kit stability out to 3 years.
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Slide 9
Control Chart of Ab42 During Development
4000
Control 1
Control 2
Control 3
3000
Concentration (pg/ml)
2000
1000
1000
750
500
300
200
100
Kit Lot 1
0
0
10
Kit Lot 2
20
30
40
Kit Lot 3
50
60
70
Run
Ab42 levels were measured in matrix-based controls (n=3). Measurements were made across three kit
lots using multiple analysts and plates during runs over a five month period. Left: Results for the three
controls, tested on kit lots 1–3, are presented. Dotted lines represent two standard deviations above
and below the assigned concentration. Right: The precision results for the controls are presented.
Reported concentrations are adjusted for sample dilution.
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Slide 10
Concentration (pg/ml)
Control Chart of Total Tau During Development
6000
5000
4000
3000
2000
Control 1
Control 2
Control 3
1500
1250
Control
1
Control
2
Control
3
1000
n
71
71
71
750
500
Conc
(pg/mL)
4355
1130
292
Std Dev
543
95
45
%CV
12%
8%
15%
250
Kit Lot 1
0
0
10
Kit Lot 2
20
30
40
Kit Lot 3
50
60
70
Run
Total tau levels were measured in matrix-based controls (n=3) across three kits lots, and multiple
analysts, plates, and runs over a period of seven months. Reported sample concentrations are
adjusted for sample dilution. Left: Results for the three controls, tested on kit lots 1–3, are presented.
Dotted lines represent two standard deviations above and below the assigned concentration. Right:
The precision results for the controls are presented.
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Slide 11
Clinical Utility Results
Ab42
T-Tau
*
*
*p<0.05 compared control
*
*
*p<0.05 compared control
T-Tau/Ab42 Ratio
*
*
*p<0.05 compared control
Sunday: P1-322
 49 Normal, 50 MCI, and 50 AD samples
 Established Cut-offs for this Data Set
 Samples run at two dilutions to show linearity
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Slide 12
Total Tau 1:2 Dilution
Concentration Difference between 1:2 and 1:4
Dilution Linearity of Total Tau Assay (149 Samples)
Total Tau 1:4 Dilution
Mean Tau Concentration
 149 samples run at 1:2 and 1:4 dilution show concordance.
 Increased sensitivity possible with Tau samples run at 1:2 fold dilutions.
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Slide 13
Ab42 1:8 Dilution
Concentration Difference between 1:8 and 1:16
Ab42 1:16 Dilution
Dilution Linearity of Ab42 Assay (149 Samples)
Cutoff :240 pg/ml
Mean Ab42 Concentration
 149 samples run at 1:8 and 1:16 dilution show concordance.
 Assay recommended to be run at 1:8, but 1:16 can be used to conserve on
sample volume.
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Slide 14
Multi-Site Validation Participants
 Training and Operator
Certification
 Multi-run validation




Minimum of 6 runs
12 Pooled CSF samples
4 AD samples
Dilution Linearity measurement
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8/17/2012
Industry
 Bristol Myers Squibb
 Meso Scale Discovery
Academic/Clinical
 Gothenburg University
 Edith Cowan University
 Additional Site TBD
Clinical Testing Lab
 Labcorp
 ICON
 QPS Bioanalytical
MSD-S00XXXX
Slide 15
MSD Aβ42 and Total Tau Certification and Proficiency Program
MSD’s commitment to quality to train and certify operators and help laboratories
show proficiency with measuring the assays.
Training and Certification: Proficiency Program
 Operators are trained to use the MSD
platform.
 Neurodegeneration Control Pak used
as part of training.
 Demonstrate ability to measure
controls with 25% accuracy and
precision.
 Operator gets training certificate
 Compliance with most Quality Systems
Available Now
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8/17/2012
 Labs demonstrate proficiency
 Control chart and reproducibility of
controls.
 Blinded CSF samples
 Report published with multiple
laboratory results
 List of proficient labs on MSD Website
Plan Now
Run mid-July 2012
MSD-S00XXXX
Slide 16
Next Steps for Alzheimer’s Portfolio




Completion of Multi-Site Validation and Publish Work
Submitted Request for ADNI samples to be tested
Support GBSC Reference Material and Methods Studies
Real Time Stability out to 30 Months.
 Validation of Multiplex Assays: Ab38, Ab40, Ab42
 Focus on Related Markers
 Plasma Biomarkers
 Traumatic Brain Injury
 Parkinson’s Disease
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Slide 17
Acknowldegements
Bristol-Meyers Squibb
 Flora Berisha
 Carol Gleason
 Oi Wong
 George Green
 Robert Neely
 Holly Soares
 Paul Rhyne
 Jane Tiller
 Steve Piccoli
AJ Simon Enterprises, LLC
 Adam Simon
Meso Scale Diagnostics
 Jill Dunty
 Leonid Dzantiev
 Mwanatumu Mbwana
 Sara Hapip
 Qian Ning
 Franklin Braffett
 Sarah Robles
 James Wilbur
 Robert Umek
 Pankaj Oberoi
 David Stewart
 Jacob Wohlstadter
University of Gothenberg Alzheimers
Association QC program
MSD Confidential and Proprietary
8/17/2012
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Slide 18