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TRANSCRIPT
VNS Update:A Look Into the Future
Shaun Comfort MD, MBASr. Director, Clinical Affairs
Cyberonics, Inc.
AED XI Conference
Agenda•VNS Today
–Epilepsy: Efficacy & Safety Rates
•VNS Tomorrow–Seizure Response: “Automatic Magnet Mode”
•Manual VNS Stimulation Has An Effect•What Is Ictal Tachycardia?•Next Steps
•Beyond VNS–Cyberonics of the future
VNS Today
• Mild pulses applied to vagusnerve in neck send signals tobrain
• Adjustable, automaticintermittent stimulation
Technology
• Placed subcutaneously in chest• Pulse –3rd generation• DemiPulseTM –4th generation
Generators Leads
• 302 base model• PerenniaTM lead
– Increased durability• Perennia FlexTM lead
–More flexible Perennia lead
Vagus Nerve Stimulation (VNS) Therapy: HC Device
4
AspireHC™ Generator
•5th generation platform•Extended battery life•Improved electronics•Simplified features for
programming•Limited US commercial
release in progress
Current VNS Epilepsy Therapy® –Clinical TrialExperience
Source: Epilepsy Physician’s Manual NCP, Cyberonics
•VNS Efficacy is well established in multiple controlled clinical trials
•Since approval in 1997, 80,000+ implants
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•A patient “responder” has 50% reduction in seizure frequency frombaseline
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
3 months 1 year 2 years 3 years
Morris GL, et al. Neurology 1999;53:17315.
23%
37%43% 43%
% R
esp
on
ders
Proportion of Responders(n=440, LOCF)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Vonck(n=118)
Renfroe(n=120)
Labar(n=269)
DeHerdt(n=138)
% R
esp
on
ders
Mean F/U 33 mo 3 mo 12 mo 44 mo
59%57%51%50%
1. De Herdt V, et al. Eur J Paediatr Neurol 2007;11:2619.2. Labar DR. Seizure 2004;13:3928.3. Renfroe JB and Wheless JW. Neurology 2002;59(suppl 4):S26S30.4. Vonck K, et al. J Clin Neurophysiol 2004;21:2839.5. Elliott R, et al. AES Presentation 2009.
•Clinical Trial Responder Rates •Single Center Experiences
Proportion of Responders
67%
58 mo
Elliott(n=436)
Current VNS Epilepsy Therapy® –Long Term ClinicalExperience
•Observational data suggests a time dependent, sustained increase in theproportion of VNS responders
Current VNS Epilepsy Therapy® –Clinical Trial Experience29%
7%
12%
8%
6%
4%3%
2% 2%
0%
3%
19%
0%
5%
10%
15%
20%
25%
30%
Hoarseness Cough Paraesthesia Shortness ofbreath
% P
ati
en
ts
1 year
2 years
3 years
1. Morris GL, et al. Neurology 1999;53:17315.
VNS TomorrowH. Wang et al; “six auras and threeseizure attacks in three of the eightpatients happened to be recordedduring videoEEG monitoring . . . theseattacks were terminated by the extrastimulation of VNS with a handheldmagnet.”
Sum: Periodic/prophylactic stimulationcan be effectively supplemented byjudicious use of the magnet.Wang H, et al. J. Neuro Scinences 2009;(284):96102
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Patients report a decrease in theseverity/duration of their seizures usingthe VNS Therapy magnet
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Positive impact on seizure activity5,849 seizures
Seizure not effected 3,633 seizures
PRO Effects of MagnetActivated Stimulation in 9,482
Seizures
62%
38%
24%
Seizurediminution
3,638seizures
Morris GL, et al. Epilepsy Behav 2003;(4):740745.
•Offers more control forpatients and theirfamilies1,2
•Initiates on demandstimulation
–May abort or decreaseseverity of seizures13
–May improve postictalperiod2
•Stops stimulation–Acutely manage side
effects3
Ondemand magnet stimulation aunique benefit of VNS Therapy
1. Boon P, et al. J Clin Neurophys. 2001;18:402407.2. Fromes GW, et al. Epilepsia. 2000;41(suppl 7):117.3. Schachter SC and Saper CB. Epilepsia. 1998;39:677686.
Seizureterminated
2,211seizures
Seizures Not Affected(3633)
Seizures Affected(5849)
38%
An Aside: Why “On Demand” VNS Stimulation
VNS Tomorrow•Manual Magnet Induced Stimulation:
– Works “well” for patients with obvious event onset (e.g.,stereotypical auras, etc)
– What about for patients without preceding auras, caregivers?
•Automate the Manual Stimulation (AMM):– Rationale:
• “Automate” the manually triggered VNS stimulation (i.e.,Manual Magnet Mode or MMM)
• Link additional VNS stimulation to onset of clinical event• Use “Ictal Tachycardia” as biomarker for partial complex
seizures, in patients demonstrating this
What Is Ictal Tachycardia (ICT)?Definitions:
– No standard definition but generally defined as cooccurrence of sinustachycardia with ictal events.
– Definitions employ percentage HR increases during ictal eventscompared to resting or preictal HR
Mechanism:– Unclear possibly due to ictal discharges stimulating brainstem cardiac
centers. May explain observation of high incidence of ictal tachycardiawith right > left mesial temporal lobe epilepsy.
Examples:– Kielson et al. Arch Neurol 1989;(46)– Nilsen et al. Seizure 2010;(19):291295
Kielson, et al. 1989: ECG Changes DuringSZs
Relative Ictal HR Increase(Baseline to Peak)
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
010 1150 51100 100+
% Increase Relative to Baseline HR
% o
f Tot
al S
Zs
Source: Kielson et al. Electrocardiographic Changes During Electrographic Seizures. Arch Neurol , 46, 1989.
Result: CYBX Working Definition of ICT
• Comments: ICT Definition– Operational, based on
clinical findings
– Possesses clinical “Facevalidity”
– Results in reasonablespecificity
• Comments: SR Algorithm– Based on HR changes
relative to baseline,associated with Ictal Events
– At higher relative HRthresholds, performs similar toCYBX ICT working definition
• If MAXHR 100 bpm AND ((delta 35 bpm) OR (delta 55%)) then– Ictal Tachycardia is Present
• else– Ictal Tachycardia is NOT present
One Episode of ICT from EEG/ECGDatabase
Ictal Electrographic Onset (EO)Instantaneous HR
Y –Axis: HR (bpm); X –Axis: Time (min)
Event with ICT: TriggersStimulation When DetectionThreshold met
This graphic illustrates a time series tracing of instantaneousHR with a superimposed time stamp for EO. The coincidenttachycardia peak is observable within the dashed window.
Illustration of EEG and ECG Concurrence
CYBX SR: Next StepsClinical Trials:
– First In Man study initiated in Europe•Medically refractory Epilepsy patients exhibiting ICT•EMU based study•Evaluation of Performance and Tolerability
– US: Protocol development underway for future IDEsubmission
Beyond VNS
18
AspireSR
Phoenix
Griffin
AspireNP
MRI Conditional System
Key Technology: MicroBurst Stim + OtherCollaboration: Barrow Neurological InstituteElectronic Diary
Telemedicine
Sz Alert
•Acceleration of product developmentpipeline
•Introduction of novel closedloop VNStherapy
Note: Except AspireHC, products shown above are Not Approved for Human Use.
Key Technology: EEG Sensing + OtherCollaboration: MIT, Purdue, Neurovista
Key Technology: Leadless ElectrodeCollaboration: Purdue
CYBX 2014(CYBX of the future)
CYBX today
VNS Therapy® –Future Pipeline
Innovation:• Rechargeable• Wireless• Telemedicine• Remote monitoring• New parameters• Detect/predict
RecordAlertNotifyTherapy
Key Technology:Extended Longevity
Key Technology: Closed Loop Sz ResponseCollaboration: Flint Hills Scientific
AspireHC
End