A precompetitive consortium to validate advanced EEG/ERP biomarkers for use in interventional CNS trials.

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
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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
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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
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 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.
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