Martha J. Morrell MD NeuroPace, Inc. The NeuroPace® RNS System: Clinical Development of Responsive Cortical Stimulation as a Treatment for Medically Refractory Epilepsy Martha J. Morrell MD NeuroPace, Inc.

NeuroPace Overview Founded in 1999 to design, develop, manufacture and market implantable responsive neurostimulation devices for treating epilepsy by direct brain stimulation

The RNS™ System Approach Detect abnormal brain electrical activity with electrodes implanted near the area of seizure onset Stimulate at the time of detection and before a seizure develops Program detection and stimulation for individual patient Transmit device and electrocorticogram data to interactive web-based repository View data on-line at any time to assess clinical response

The RNS™ System Cranially implanted battery powered responsive neurostimulator Connected to 2 leads (depth and/or subdural) with 4 electrode contacts each

The RNS™ System Neurostimulator detects and stimulates abnormal brain electrical activity with implanted electrodes Programmer sets detection and stimulation parameters Programmer and Patient Data Transmitter send ECoG data to web-based repository for review

Patient Data Management System Caution: Investigational Device. Limited by US Law to Investigational Use Only.Caution: investigational device. Limited by US law to investigational use only.

Overview: RNS System Clinical Trials in Epilepsy Feasibility Trial: completed Pivotal Trial: on-going Long-term Treatment Trial: 5 year follow-up all subjects

RNS™ System Feasibility Investigation Designed to assess safety of the RNS™ System and to show preliminary evidence for efficacy as an adjunctive therapy in reducing the frequency of seizures in individuals 18 years of age or older with partial onset seizures that are refractory to two or more antiepileptic medications Multi-center investigation 3

RNS™ System Feasibility Investigation: Inclusion Criteria 18 to 65 years of age with disabling simple, complex partial and/or generalized tonic clonic seizures Failed treatment with 2 or more antiepileptic drugs 4 or more simple, complex or secondarily generalized TC seizures/month One or two localized epileptogenic zones 3

RNS™ System Feasibility Investigation: Trial Design Implant RNS System 1 2 3 4 24 months Therapy ON -n Therapy OFF Baseline: > 3 months Post-Implant: 28 days Evaluation: 3-28 day periods Follow-up: 24 months post-implant After 2 year Feasibility trial, subjects transition to Long-term Treatment Trial for additional 5 year follow-up

Responder Rate During Efficacy Evaluation Period (2-4 Months Post-Implant, N= 50*) Responder Rate: patients with > 50% reduction in seizure frequency over most recent 84 days vs. baseline All disabling seizures* 24% (12/50) Complex partial seizures 27% (12/44) Generalized TC seizures 65% (11/17) Disabling seizures= SPM, CPS and GTC *5 subjects excluded due to inconsistencies in the data, 1 had no disabling seizures at baseline, 14 subjects randomized to sham stimulation

Responder Rate Over Most Recent 84 Days of Data (N = 59 Responder Rate Over Most Recent 84 Days of Data (N = 59*): All Disabling Seizures Analysis by seizure onset location Total 47% Hippocampal 74% Neocortical 34% * 5 subjects excluded due to inconsistencies in the data, 1 had no disabling seizures at baseline Data are current as of 11/2008; not completely verified.

Feasibility: Response over Time FS - Data updated as of 6/24/2008 – Note: the OFF patients were shifted by 111 days so the 3MO data represents 3MO after they were turned ON. Data are current as of 02/19/2009; not completely verified.

RNS™ System Feasibility Investigation: Summary Experience Safety milestone reached No unanticipated device related or surgery related serious adverse events Preliminary evidence for efficacy Reduction in SP motor, CPS, GTC seizures Subjects with hippocampal onset had especially good response

RNS™ System Pivotal Trial Randomized, double-blinded, multi-center, sham stimulation controlled 240 patients enrolled at 29 sites Objective Demonstrate that the RNS System is safe and effective in reducing the frequency of disabling seizures in adults with medically intractable partial onset seizures

RNS™ System Clinical Experience All epilepsy trials combined 310 subjects enrolled 246 subjects implanted > 426 patient years of post-implant experience > 367 patient years of stimulation experience FS – updated implant years and stim years as of 6/24/2008 Data current as of March 3, 2009; not completely verified.

RNS™ System Clinical Trials in Epilepsy Technology successful Safety profile appears favorable No unanticipated device related serious adverse events Feasibility trial shows evidence for durable efficacy Future plans Pivotal trial complete in August 2009 Analysis of clinical response as a function of Detection and stimulation programming Epileptogenic region Epilepsy etiology