Presentation Materials

Cortical Stimulation for the Treatment of

Motor Deficit following Ischemic Stroke

Robert M. Levy, MD, PhD

Professor of Neurological Surgery

Feinberg School of Medicine

Northwestern University

Exhibit 99.3

Disclosures

•

Study Sponsor: Northstar

Neuroscience,

Seattle, WA

•

RML: Research Grant Support, Consultant

•

Caution: Investigational device. Limited by

Federal (or U.S.) law to investigational use.

Concept: Cortical Stimulation for

Stroke Recovery

•

Cerebral cortex has the ability to reorganize

synaptic connectivity in response to injury –

neuroplasticity

•

When combined with rehabilitation, cortical

stimulation may facilitate neuroplasticity and

improve function

Neuroplasticity: Shown by Functional

Magnetic Resonance Imaging (fMRI)

Tissue damaged by stroke

Results in loss of motor

function

Alternative Pathway

Other areas of the brain assume

some function for the damaged area

Pre-Clinical Studies of Cortical

Stimulation for Stroke Recovery

Rodent

G. Campbell

Teskey, PhD

University of

Calgary

Randy Nudo, PhD

Jeff Kleim, PhD

T. Jones, PhD

Investigator

Primate

Rodent

Model

University of Texas,

Austin

University of

Lethbridge

University of Kansas

Institution

Preclinical Studies:

Montoya Staircase Test Apparatus

Food retrieval task

Source: T. Jones (U of Texas, Austin) and G.C. Teskey (U of Calgary)

Stimulation During Training vs.

Control

Days of Post-Implant Training

Pre-Stroke Performance

Training only

Source: T. Jones (U of Texas, Austin)

Behavioral Performance:

Stimulation During Training Restores Rats

to Pre-Stroke Performance

Stimulation During Training vs.

Control

Days of Post-Implant Training

Pre-Stroke Performance

Training only

Stimulation

during training

Source: T. Jones (U of Texas, Austin)

Behavioral Performance:

Stimulation During Training Restores Rats

to Pre-Stroke Performance

Pre-Clinical Studies in Rats

Pre

Rehab Session

Rehab only

CS during Rehab

CS before Rehab

CS must be concurrent with rehabilitation

Source: G.C. Teskey (U of Calgary)

Source: R. Nudo (KUMC)

•

Food retrieval task

•

Tests average time to retrieve pellets from series of wells

Primate Studies

Neurophysiological Mapping Techniques (ICMS)

Source: Plautz et al, Presented at the International Stroke Conference, 2005

PMD

SMA

PMV

2 mm

HAND

PMV

FACE

LATERAL

ROSTRAL

2 mm

MICROFORCEPS

ISCHEMIC AREA

CENTRAL

SULCUS

INFARCT

BORDER

PRE-INFARCT

POST-INFARCT

% Recovery Relative to Pre-Infarct Performance Level

•

CS/RT = Cortical Stimulation + Rehabilitative Training, RT =

Rehabilitative Training only

•

% recovery relative to baseline measured using dwell time

performance during therapy

•

CS/RT produced greater maximum recovery level than RT

20%

40%

60%

80%

100%

RT (n=5)

CS/RT (n=3)

EXPERIMENT WEEK

Therapy

88%

max recovery

56%

max recovery

•

Therapy initiated 4 months post-stroke

•

Significant improvements maintained at 6 month follow-up

•

Replicated in subsequent studies

0.0

0.5

1.0

1.5

2.0

2.5

Pre-lesion

Pre-therapy

Post-therapy

Follow-up

59%

improvement

Longevity of Functional Improvements,

Primate Chronic Stroke Model

Source: R. Nudo (KUMC)

Cortical Stimulation + Rehabilitative Training

Summary of Pre-Clinical Studies

•

Consistent results were achieved across 2 species

(rodent and primate) and 3 ischemic stroke models

•

Studies demonstrated that cortical stimulation

–

Is safe

–

Significantly improves recovery of function compared to

control

–

Shows benefit with both bipolar and monopolar stimulation

–

Is effective when administered months after stroke

–

Achieves gains that are significant and are retained for

months beyond treatment

•

Optimal electrical stimulation parameters evaluated

•

Mapping studies indicate cortical reorganization

ADAMS

(2003)

Phase I

BAKER

(2004)

Phase II

EVEREST

(2008)

Pivotal

Cortical Stimulation for Stroke Recovery

Clinical Trials

Safety

N = 8

3 US sites

Safety &

Efficacy

N = 24

9 US sites

Safety &

Efficacy

N = 151

21 US sites

Combined ADAMS and BAKER:

Improvement in Upper Extremity Fugl-

Meyer (UEFM)

ANOVA:

Overall P<0.001, group by assessment interaction P=0.04.

P=0.01 compared with control group by t-test.

UEFM Score: Change From Baseline

Statistically significant improvements in function

Baseline

Investigational Group

Control Gro

Follow-Up

Week 4

Follow-Up

Week 12

Clinically

Meaningful

Patients with Clinically Meaningful Changes

(>3.5 points) in UEFM: Combined ADAMS and

BAKER

P=0.01 compared with control group by chi-square test.

Patients with Clinically Meaningful Improvement in UEFM Score

75%

81%

31%

38%

20%

40%

60%

80%

100%

Follow-Up Week 4

Follow-Up Week 12

Investigational Group

Control Group

75% of cortical stimulation patients showed improvement

Evidence of the Brain’s Response to Cortical

Stimulation Therapy using fMRI: Overview

•

ADAMS

study

–

MRI

analysis

was

performed

baseline and after completion of the 3 week

rehabilitation protocol.

•

Patients performed the same motor task at each fMRI

session: index finger tapping or wrist extension

•

The fMRI activation maps for each group (control group

or the investigational group) were compared to identify

changes in activation resulting from therapy

•

Results published in Stroke

May 2005

MRI

Consolidation

Results

•

The investigational group showed a reduced volume of activation

post-therapy, while the control group showed almost no change

•

The consolidation of activation seen in the investigational group

resembles events seen during spontaneous recovery from stroke

Consolidation

of activation

Caution:

Investigational device. Limited by federal (or US) law to investigational use

Case Study (Patient 1)

American Academy of Neurology 4/07, Helmi Lutsep

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

UEFM

AMAT

SIS Hand

SIS

Recovery

Baseline

12 weeks

3 years

Performance upon initiating

ADAMS study (Baseline), 12

weeks after receiving

investigational CS and

rehabilitation, and 3 years later.

Results are normalized to the

maximum score (normal function)

for each outcome measure.

Conclusion:

The

effects

plus

rehabilitation

not

only

persisted

for

years

but

showed

further

gains

function.

Cortical Stimulation for Stroke Recovery

•

Pre-clinical and feasibility clinical trials leading up

to EVEREST

trial

–

Have shown safety

–

Have suggested that cortical stimulation combined

with rehabilitation significantly improves hand/arm

function compared with rehabilitation alone

–

fMRI

has shown that cortical stimulation consolidates

activation in the stroke affected hemisphere while the

control group showed no significant changes

Study Design

•

Prospective, randomized, single-blinded, multi-center pivotal trial

•

Patients randomized into two cohorts: investigational or control

•

152 subjects

•

94 investigational (implant)

•

58 control (no implant)

•

Investigational cohort implanted with epidural stimulation system and

given sub-threshold cortical stimulation concurrent with rehabilitation

therapy

•

Both cohorts subjected to same quality and quantity of rehabilitation (2-

2.5 hours per day, 65 total hours over 6 weeks)

•

Study was FDA and IRB approved

EVEREST –

High-Level

Protocol Summary

Subject

Referral

Phone

Screen

Informed

Consent

Entry Criteria

Evaluation

Rehab

Screen

fMRI

Baseline

Evaluation

Randomi-

zation

Control Arm

Investigational Arm

Device

Implant

Rehab w/o

Stimulation

Follow-Up

Weeks 9-24

Follow-up

Weeks 1-8

Device

Removal

Follow-up

Weeks 1-8

Rehab and

Stimulation

Enrolled

Randomized

EVEREST Clinical Sites

Spaulding

/ MGH

Wayne

State

U. AZ

U. Utah

Houston

CNI /

Swedish

OHSU

U. Florida

Jacksonville

U. Cinn

U. Pitt

U. Penn

SUNY

USC

UCSF

Mt. Sinai

Stanford

UIC

St. Luke’s

Swedish

Emory

Cortical Stimulation System

•

fMRI used to identify activation

site for hand

•

Epidural electrode placed over

cortical target indicated by fMRI

•

Implantable pulse generator

•

Overnight hospital stay

•

Subthreshold stimulation

delivered only during

rehabilitation

•

Patient does not feel stimulation

Caution:

Investigational device. Limited by

federal (or US) law to investigational use.

Stimulation Site Identification

•

Locate site of cortical activation

associated with hand function

•

Neuronavigation based on fMRI

data used to identify stimulation

site

Region of stroke

Neuroplastic area associated

with hand function

Inclusion Criteria (Partial List)

•

Ischemic vascular stroke that is:

–

Above the level of the midbrain

–

At least 4 months old

–

Documented by CT or MRI

•

Index stroke is most recent stroke

•

Medically and neurologically stable

•

Moderate to moderately severe upper-extremity hemiparesis:

–

UEFM 28-50

–

Active wrist extension of 5º

or repetitive grasp

•

Age 21 years or older

Exclusion Criteria (Partial List)

•

Primary hemorrhagic stroke

•

Any additional stroke (other than index stroke) associated with

incomplete motor recovery

•

History of seizure disorder

•

Moderate to severe hemispatial neglect and/or anosognosia

involving the affected limb

•

Severe sensory deficit

•

Contraindication to stimulation system placement surgery

Primary Outcome Measures

0.21 point improvement

4.5 point improvement

Clinically

Meaningful

0-5 points

higher score = better performance

0-66 points

Higher score = better function

Score

Range

Activities of Daily Living (ADLs)

scored for speed, function and

quality of movement

Hand/arm function

(9 components of neurologic

and motor function)

What is

Measured

Arm Motor Ability Test

Upper Extremity Fugl-Meyer

UEFM

AMAT

UEFM + AMAT

Investigational

Control

20%

Primary Endpoint Analysis

•

UEFM:

subjects

with

clinically

meaningful improvement (

4.5) at 4

weeks following therapy

AND

•

AMAT:

subjects

with

clinically

meaningful improvement (

.21) at 4

weeks following therapy

•

Definition of Success:

The % of

investigational subjects that achieve

improvement is at least 20 percentage

points more in absolute terms than

control subjects

EVEREST: Adverse Events

# SAEs

Procedure Related

Device Related

Serious AEs (total)

# Pts.

Total

N = 164

Control

N = 60

Investigational

N = 104

* Seizure occurred during patient rest day (no stimulation)

Device and Procedure related events are a subset of the overall SAE total

Safety

•

14 procedure-related SAE’s

–

4 infection

–

4 pain/HA/nausea

–

6 others (clinically sig bleeding between skull and brain, PE with

pre-existing thrombophlebitis, PVC’s, fibrous tissue build up that

was biopsied, cystoscopy for Foley placement)

•

One death—surgical arm

–

76 days after device explant (stroke with resp. failure)

•

75% of unrelated SAE’s occurred >30 days post-explant

Cortical Stimulation continues to indicate

a good safety profile

EVEREST Composite Primary

Efficacy Endpoint

Composite Primary Efficacy Endpoint Outcome:

The

percentage of investigational patients that achieved a clinically meaningful

result for both the UEFM and AMAT at the 4-week endpoint

29.1%

Control

31.9%

Investigational

Total

Success

UEFM + AMAT

Investigational

Control

31.9%

29.1%

UEFM

4.5

AMAT

0.21

Secondary Analysis of Primary

Endpoint –

Week Four

0.33

0.5

2.8

(6.0)

21.8

(12.2)

19.7

(12.4)

3.3

(5.0)

22.5

(12.4)

18.9

(11.1)

Box & Block

Mean

(SD)

0.17

0.11

0.26

(0.37)

3.27

(0.75)

3.02

(0.69)

0.37

(0.47)

3.36

(0.71)

2.97

(0.68)

AMAT

Mean

(SD)

0.33

0.3

4.0

(4.3)

41.2

(7.4)

37.6

(5.7)

4.3

(5.3)

42.0

(8.5)

37.6

(6.1)

UEFM

Mean

(SD)

Adjusted

p–value*

Difference

Mean

Change

N=55

Endpoint

N=55

Baseline

N=58

Change

N=91

Endpoint

N=91

Baseline

N=94

Investigational

Control

* 1-sided, p-value adjusted for multiplicity

UEFM: Investigational and Control

Mean Scores

4, 12, 24 weeks

3.8

4.6

4.0

Control

Mean Change in UEFM Score from Baseline

4.8

weeks

4.6

weeks

4.3

Investigational

weeks

Long-Term Data:

UEFM, Full Analysis Population

UEFM Mean Scores vs Time

Baseline

4 weeks

12 weeks

24 weeks

Investigational

Control

p = 0.62*

Overall treatment effect

* Repeated Measures Analysis

AMAT Mean Scores vs Time

2.9

3.1

3.2

3.3

3.4

3.5

3.6

Baseline

4 weeks

12 weeks

24 weeks

AMAT: Investigational and Control

Mean Scores

at 4, 12, 24 weeks

0.17

0.26

Control

Mean Change in AMAT Score from Baseline

0.36

12 weeks

0.35

weeks

0.37

Investigational

4 weeks

Long-Term Data:

AMAT, Full Analysis Population

Investigational

Control

p = 0.12* Overall treatment effect

p = 0.02*

Treatment effect at 24 weeks

* Repeated Measures Analysis

What Is the Motor Threshold

Subset?

•

Motor threshold (MT) test performed to evoke hand

movement

•

Stimulation current set to 50% of MT if achieved, else set

to maximum device output

•

MT performed 3 times throughout rehab protocol (Day 1,

Day 6 and end of rehab)

•

13 of 94 investigational patients (13.8%) achieved a

repeatable motor threshold

Motor Threshold Subset Analysis

29.1%

Control

69.2%

Investigational

Total

Success

Composite Primary Efficacy Endpoint :

The percentage of

investigational patients that achieved a clinically meaningful result for both

the UEFM and AMAT at the 4-week endpoint

p = 0.002*

* Post-hoc analysis, 1-sided p-value

UEFM + AMAT

Investigational

Control

69.2%

29.1%

Treatment Difference:

Investigational

–

Control

40.1%

Motor Threshold Subset Analysis:

Week Four

0.24

1.2

2.8

(6.0)

21.8

(12.2)

19.7

(12.4)

4.0

(4.0)

26.5

(11.7)

22.5

(12.1)

Box & Block

Mean

(SD)

0.04

0.25

0.26

(0.37)

3.27

(0.75)

3.02

(0.69)

0.50

(0.42)

3.55

(0.73)

3.05

(0.73)

AMAT

Mean

(SD)

0.02

3.2

4.0

(4.3)

41.2

(7.4)

37.6

(5.7)

7.2

(3.3)

45.6

(7.6)

38.3

(5.0)

UEFM

Mean

(SD)

Adjusted

p–value*

Difference

Mean

Change

N=55

Endpoint

N=55

Baseline

N=58

Change

N=13

Endpoint

N=13

Baseline

N=13

Investigational

Control

* 1-sided, p-value adjusted for multiplicity

UEFM: Investigational and Control

Mean Scores

at 4, 12, 24 weeks

3.8

4.6

4.0

Control

Mean Change in UEFM Score from Baseline

6.5

12 weeks

6.1

weeks

7.2

Investigational

4 weeks

Long-Term Data:

UEFM, Motor Threshold Subset

UEFM Mean Scores vs Time

Baseline

4 weeks

12 weeks

24 weeks

Investigational

Control

p = 0.07*

Overall treatment effect

p = 0.01*

Treatment effect at 4 weeks

* Repeated Measures Analysis

AMAT: Investigational and Control

Mean Scores

at 4, 12, 24 weeks

Long-Term Data:

AMAT, Motor Threshold Subset

AMAT Mean Scores vs Time

2.9

3.1

3.2

3.3

3.4

3.5

3.6

Baseline

4 weeks

12 weeks

24 weeks

Investigational

Control

0.17

0.26

Control

Mean Change in AMAT Score from Baseline

0.45

12 weeks

0.46

weeks

0.51

Investigational

4 weeks

p = 0.04*

Overall treatment effect

p = 0.03*

Treatment effect 24 weeks

* Repeated Measures Analysis

Conclusions

•

Cortical Stimulation appears safe as anticipated

•

Data suggest rehabilitation for chronic stroke patients can

make a difference (at least acutely)

•

EVEREST

did

NOT

meet

its

primary

efficacy

endpoint

Conclusions

•

Inability to evoke motor activity with CS suggests:

•

Improper targeting or electrode placement

•

Inadequate power of stimulation system

•

Inability to sufficiently stimulate cortex due to subdural

CSF and cortical depth (atrophy, deep sulcal

target)

•

Complete functional transection

of corticospinal

tract

Conclusions

•

Subjects in whom movement was evoked with CS showed

significantly superior results as compared to controls

•

Additional imaging analysis currently underway

•

Results call for follow-up studies addressing these

important issues

•

CS for stroke related motor deficit may have important

clinical applications