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Scalable Implementation and FDA Qualification of
Event-Related Potential Biomarkers for
Drug Development in Schizophrenia
—
A Pre-Competitive Consortium
The ERP Biomarker
Qualification Consortium
The ERP Biomarker Qualification Consortium
ERP Biomarker Qualification
Consortium
Founding Members
Principle Members Advisory Members
• Daniel Javitt, MD
Director, Schizophrenia Research,
Nathan Kline Institute
• Daniel Mathalon, MD
UCSF, Professor, Psychiatry, Weill
Institute for Neurosciences
• Richard Keefe, PhD
CEO, NeuroCog/VeraSci
• William Potter, MD
NIMH
• David Walling, PhD
CEO, CNS Network
• Larry Ereshefsky, PharmD
CSO, Hassman Research Institute
The ERP Biomarker Qualification Consortium
Event-Related Potential (ERP)
 ERP deficits in schizophrenia reflect cortical synaptic
pathophysiology, such as NMDA receptor hypofunction.
 ERPs are changes in the EEG
caused by sensory and
cognitive processes.
 ERPs are generated by post-
synaptic potentials in cortical
neurons.
The ERP Biomarker Qualification Consortium
Reproducibly Impaired in Schizophrenia
P300
Mismatch Negativity (MMN)
Light 2015 Schiz Res
Ford 2008 Brain Res
Javitt 2015 Nature Rev Neurosci
Auditory
Steady-State
Response
(ASSR)
Roach 2013 Clin Neurophys
40 Hz
The ERP Biomarker Qualification Consortium
Implementation in Schizophrenia Drug
Dev
 Enables translational pharmacology to detect
target engagement
 Causally predictive of registration endpoints
(cognitive and negative symptoms, global function)
 Possibly enables stratification by “Biotype” (Javitt.
2018)
The ERP Biomarker Qualification Consortium
Translational Pharmacology – MMN Impaired
by NMDAr Antagonists Across Species
Human
Umbricht 2000 Arch Gen Psych Rat Gil Da Costa 2013 PNAS
Primate
ketamine
vehicle
The ERP Biomarker Qualification Consortium
NMDAr Positive Allosteric Modulator
Rescues Impaired MMN Amplitude
- 5 0 0 5 0 1 0 0 1 5 0 2 0 0
- 3 0
- 2 0
- 1 0
0
1 0
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T i m e ( m s )
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0
1 0
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3 0
T i m e ( m s )
A
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l
i
t
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(
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P C P + C A D - 8 6 8 8
- 5 0 0
- 4 0 0
- 3 0 0
- 2 0 0
- 1 0 0
0
M
M
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(
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m
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B a s e l i n e
* *
*
- 5 0 0
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0
M
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A
U
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(
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B a s e l i n e V e h i c l e
s u b - c h r o n i c P C P
* *
*
* P<0.05 vs Baseline
** P<0.01 vs Vehicle
- 5 0 0
- 4 0 0
- 3 0 0
- 2 0 0
- 1 0 0
0
M
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1
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B a s e l i n e C A D - 8 6 8 8
V e h i c l e
s u b - c h r o n i c P C P
* *
*
The ERP Biomarker Qualification Consortium
Causally Predictive of Registration
Endpoints
JAMA Psychiatry 2017;74(1):37-46.
“…an intervention producing a 1-SD
improvement in the mean amplitude of
MMN would produce Cohen d
improvements of 0.78 for cognition and
0.28 for psychosocial functioning.”
The ERP Biomarker Qualification Consortium
• 16 stable schizophrenia patients
• 6 week treatment with D-serine
(60 mg/kg/d) vs. placebo (X-over)
• Significant D-serine effect
MMN (d=2.63, p=.001)
Symptoms (d=.8, p=.023)
Sensitive to Therapeutic
Intervention
The ERP Biomarker Qualification Consortium
Stratification of Schizophrenia Population
Biotype 1
• Deficits in sensory
processing and
cognitive control
• Enriched in inpatients
Biotype 2
• Deficits in cognitive
control
• Enriched in outpatients
Potentially Differentially Response to Novel Treatments
Am J Psychiatry 2017
The ERP Biomarker Qualification Consortium
Why haven’t ERPs been more widely
adopted in drug development?
 Low ERP signal-to-noise ratio (SNR) due to electronics, and methods.
 Lack of standardized ERP equipment, methods, procedures, analyses,
data management.
 Limited ability to aggregate ERP data from multiple sites.
 Complicated ERP equipment difficult for non-experts to use.
 Lack of validated normative ERP datasets.
 Limited exposure of CRO/sponsor to realtime study activities and data.
The ERP Biomarker Qualification Consortium
Consortium Objectives
• Optimized equipment and protocols maximize SNR, increasing power
• Standardized methods yield reproducible results across multiple sites
• Normative datasets in patients and healthy controls enable trial design
• Cloud-based data management and analytics yield real-time access to
facilitate implementation in large-scale trials
• Regulatory qualification of ERPs for use as pharmacodynamic and
predictive biomarkers
The ERP Biomarker Qualification Consortium
COGNISION®
An FDA-cleared, High Performance, Fully Automated ERP System
● Advanced Active Electrode Headset
– Maximum signal-to-noise (SNR)
● Wireless and Battery-powered
– Extreme portability
 Convenient HydroDot Biosensors
− Easy and quick set-up
 Standardized Protocols
− Reliable and repeatable
 EEG, ERP, and Audiometry
− All tests performed in single session
 Automated Analysis
− Near realtime evaluation of test results
 Clinical Study Module
− Task management
− Realtime exposure for sponsor/CRO
● Online Data Management
− Centralized storage of all subject and test data
13
The ERP Biomarker Qualification Consortium
COGNISION® Cloud
Available, Scalable, and Secure
The ERP Biomarker Qualification Consortium
Consortium Studies
 EBS-A (ongoing):
Schizophrenic vs Healthy
Controls
◦ 80 each
◦ Multiple Sites
◦ ERPs: MMN, P300, ASSR
◦ Psychometric Assessments:
PANSS, BACS, UPSA
◦ Objective: Evaluate test/re-test and
site-site variability, generate
normative datasets
15
 EBS-B:
Ketamine Challenge
◦ 20 Healthy Controls
◦ Single site
◦ ERPs: MMN, P300, ASSR
◦ Objective: Demonstrate
pharmacodynamic
responsiveness
The ERP Biomarker Qualification Consortium
Industry Benefits
 Reduced operational risk and cost of using ERP
biomarkers in therapeutic trials.
 Evaluate statistical power of ERP biomarkers to
optimize trial design.
 Streamlined regulatory process for trials
leveraging qualified ERP biomarkers.
16

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ERP Biomarker Qualification Consortium, NDD Summit

  • 1. Scalable Implementation and FDA Qualification of Event-Related Potential Biomarkers for Drug Development in Schizophrenia — A Pre-Competitive Consortium The ERP Biomarker Qualification Consortium
  • 2. The ERP Biomarker Qualification Consortium ERP Biomarker Qualification Consortium Founding Members Principle Members Advisory Members • Daniel Javitt, MD Director, Schizophrenia Research, Nathan Kline Institute • Daniel Mathalon, MD UCSF, Professor, Psychiatry, Weill Institute for Neurosciences • Richard Keefe, PhD CEO, NeuroCog/VeraSci • William Potter, MD NIMH • David Walling, PhD CEO, CNS Network • Larry Ereshefsky, PharmD CSO, Hassman Research Institute
  • 3. The ERP Biomarker Qualification Consortium Event-Related Potential (ERP)  ERP deficits in schizophrenia reflect cortical synaptic pathophysiology, such as NMDA receptor hypofunction.  ERPs are changes in the EEG caused by sensory and cognitive processes.  ERPs are generated by post- synaptic potentials in cortical neurons.
  • 4. The ERP Biomarker Qualification Consortium Reproducibly Impaired in Schizophrenia P300 Mismatch Negativity (MMN) Light 2015 Schiz Res Ford 2008 Brain Res Javitt 2015 Nature Rev Neurosci Auditory Steady-State Response (ASSR) Roach 2013 Clin Neurophys 40 Hz
  • 5. The ERP Biomarker Qualification Consortium Implementation in Schizophrenia Drug Dev  Enables translational pharmacology to detect target engagement  Causally predictive of registration endpoints (cognitive and negative symptoms, global function)  Possibly enables stratification by “Biotype” (Javitt. 2018)
  • 6. The ERP Biomarker Qualification Consortium Translational Pharmacology – MMN Impaired by NMDAr Antagonists Across Species Human Umbricht 2000 Arch Gen Psych Rat Gil Da Costa 2013 PNAS Primate ketamine vehicle
  • 7. The ERP Biomarker Qualification Consortium NMDAr Positive Allosteric Modulator Rescues Impaired MMN Amplitude - 5 0 0 5 0 1 0 0 1 5 0 2 0 0 - 3 0 - 2 0 - 1 0 0 1 0 2 0 3 0 T i m e ( m s ) A m p l i t u d e (  V ) b a s e l i n e - 5 0 0 5 0 1 0 0 1 5 0 2 0 0 - 3 0 - 2 0 - 1 0 0 1 0 2 0 3 0 T i m e ( m s ) A m p l i t u d e (  V ) P C P + v e h i c l e - 5 0 0 5 0 1 0 0 1 5 0 2 0 0 - 3 0 - 2 0 - 1 0 0 1 0 2 0 3 0 T i m e ( m s ) A m p l i t u d e (  V ) P C P + C A D - 8 6 8 8 - 5 0 0 - 4 0 0 - 3 0 0 - 2 0 0 - 1 0 0 0 M M N N 1 A U C (  v * m s ) B a s e l i n e * * * - 5 0 0 - 4 0 0 - 3 0 0 - 2 0 0 - 1 0 0 0 M M N N 1 A U C (  v * m s ) B a s e l i n e V e h i c l e s u b - c h r o n i c P C P * * * * P<0.05 vs Baseline ** P<0.01 vs Vehicle - 5 0 0 - 4 0 0 - 3 0 0 - 2 0 0 - 1 0 0 0 M M N N 1 A U C (  v * m s ) B a s e l i n e C A D - 8 6 8 8 V e h i c l e s u b - c h r o n i c P C P * * *
  • 8. The ERP Biomarker Qualification Consortium Causally Predictive of Registration Endpoints JAMA Psychiatry 2017;74(1):37-46. “…an intervention producing a 1-SD improvement in the mean amplitude of MMN would produce Cohen d improvements of 0.78 for cognition and 0.28 for psychosocial functioning.”
  • 9. The ERP Biomarker Qualification Consortium • 16 stable schizophrenia patients • 6 week treatment with D-serine (60 mg/kg/d) vs. placebo (X-over) • Significant D-serine effect MMN (d=2.63, p=.001) Symptoms (d=.8, p=.023) Sensitive to Therapeutic Intervention
  • 10. The ERP Biomarker Qualification Consortium Stratification of Schizophrenia Population Biotype 1 • Deficits in sensory processing and cognitive control • Enriched in inpatients Biotype 2 • Deficits in cognitive control • Enriched in outpatients Potentially Differentially Response to Novel Treatments Am J Psychiatry 2017
  • 11. The ERP Biomarker Qualification Consortium Why haven’t ERPs been more widely adopted in drug development?  Low ERP signal-to-noise ratio (SNR) due to electronics, and methods.  Lack of standardized ERP equipment, methods, procedures, analyses, data management.  Limited ability to aggregate ERP data from multiple sites.  Complicated ERP equipment difficult for non-experts to use.  Lack of validated normative ERP datasets.  Limited exposure of CRO/sponsor to realtime study activities and data.
  • 12. The ERP Biomarker Qualification Consortium Consortium Objectives • Optimized equipment and protocols maximize SNR, increasing power • Standardized methods yield reproducible results across multiple sites • Normative datasets in patients and healthy controls enable trial design • Cloud-based data management and analytics yield real-time access to facilitate implementation in large-scale trials • Regulatory qualification of ERPs for use as pharmacodynamic and predictive biomarkers
  • 13. The ERP Biomarker Qualification Consortium COGNISION® An FDA-cleared, High Performance, Fully Automated ERP System ● Advanced Active Electrode Headset – Maximum signal-to-noise (SNR) ● Wireless and Battery-powered – Extreme portability  Convenient HydroDot Biosensors − Easy and quick set-up  Standardized Protocols − Reliable and repeatable  EEG, ERP, and Audiometry − All tests performed in single session  Automated Analysis − Near realtime evaluation of test results  Clinical Study Module − Task management − Realtime exposure for sponsor/CRO ● Online Data Management − Centralized storage of all subject and test data 13
  • 14. The ERP Biomarker Qualification Consortium COGNISION® Cloud Available, Scalable, and Secure
  • 15. The ERP Biomarker Qualification Consortium Consortium Studies  EBS-A (ongoing): Schizophrenic vs Healthy Controls ◦ 80 each ◦ Multiple Sites ◦ ERPs: MMN, P300, ASSR ◦ Psychometric Assessments: PANSS, BACS, UPSA ◦ Objective: Evaluate test/re-test and site-site variability, generate normative datasets 15  EBS-B: Ketamine Challenge ◦ 20 Healthy Controls ◦ Single site ◦ ERPs: MMN, P300, ASSR ◦ Objective: Demonstrate pharmacodynamic responsiveness
  • 16. The ERP Biomarker Qualification Consortium Industry Benefits  Reduced operational risk and cost of using ERP biomarkers in therapeutic trials.  Evaluate statistical power of ERP biomarkers to optimize trial design.  Streamlined regulatory process for trials leveraging qualified ERP biomarkers. 16