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ERP Biomarker Qualification Consortium, NDD Summit

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

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ERP Biomarker Qualification Consortium, NDD Summit

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 14. The ERP Biomarker Qualification Consortium COGNISION® Cloud Available, Scalable, and Secure
  15. 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. 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

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