new treatment devices and clinical trials
TRANSCRIPT
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New Treatment Devices and Clinical Trials in Epilepsy
Kate Davis, MD, MTRAssistant Professor of Neurology, University of Pennsylvania
Medical Director of Penn’s Epilepsy Monitoring Unit and Epilepsy Surgical Program
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Treatment of Seizures
Anti-seizureDrugs
Dis
ease
Mod
ifyin
gT
hera
pies
Diminish
Enhance
Key
Excitatory
Inhibitory
GabaergicAnticonvulsants
Anti-glutamatergic Anticonvulsants
Seizure NeuromodulationLesion/NetworkSurgery
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Anticonvulsant Screening Program
Maximal ElectroShock Similar to ECT
Used to discover phenytoin
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Generic Brand Name Generic Brand Name
Phenobarbital Luminal Lacosamide Vimpat
Phenytoin Dilantin Clobazam Onfi (Frisium)
Primidone Mysoline Ezogabine Potiga
Carbamazepine Tegretol Eslicarbazepine Aptiom
Valproate Depakote Perampanel Fycompa
Felbamate Felbatol
Gabapentin Neurontin
Lamotrigine Lamictal
Topiramate Topamax
Tiagabine Gabitril
Oxcarbazepine Trileptal
Levetiracetam Keppra
Zonisamide Zonegran
Pregabalin Lyrica
Rufinamide Banzel
Vigabatrin Sabril
Anticonvulsant Screening Program
Panache.ninds.nih.gov
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Selection of Antiepileptic Drug Seizure type Epilepsy syndrome diagnosis Age Gender Concomitant medical conditions and
medications Anticipated duration of treatment Elimination (hepatic, renal) Pharmacokinetics (half-life, dosing
interval) Safety and side effect profile Cost
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Efficacy Spectrum of 1st Gen Antiepileptic Drugs
PB PRM PHT CBZ VPA FBM
Simple partial + + + + + +
Complex partial + + + + + +
Secondary GTC + + + + + +
Primary GTC + + + + + +
Myoclonic + + - - + +
Absence - - - - + +
Lennox-Gastaut + +/- +/- +/- + +
Monotherapy + + + + + +
Note: FDA approval may not exist for all seizure types for which efficacy has been demonstrated or suggested
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Efficacy Spectrum of 2nd Gen Antiepileptic DrugsPGB GBP LTG TPM TGB OXC/
ESLLVT ZNG
Simple partial + + + + + + + +
Complex partial + + + + + + + +
Secondary GTC + + + + + + + +
Primary GTC ? - + + - ? + +
Myoclonic ? - + + - - + +
Absence ? - + + - - + +
Lennox-Gastaut ? - + + - - ? ?
Monotherapy ? + + + ? + ? ?
Note: FDA approval may not exist for all seizure types for which efficacy has been demonstrated or suggested
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Efficacy Spectrum of 3rd Gen Antiepileptic DrugsRUF VGB LAC CLB EZG PER
Simple partial ? + + ? + +
Complex partial ? + + ? + +
Secondary GTC ? + + ? + +
Primary GTC ? - ? ? ? +
Myoclonic ? - ? + ? ?
Absence ? - ? + ? ?
Lennox-Gastaut + - ? + ? ?
Monotherapy ? ? ? ? ? ?
Note: FDA approval may not exist for all seizure types for which efficacy has been demonstrated or suggested
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Third Generation Common adverse effects
Rare or idiosyncratic side effects
Clobazam (Onfi) Somnolence, anxiolytic, drooling
Repiratory failure
Esliscarbazepine (Aptiom)
Dizziness, GI effects, hyponatremia
Rash, SJS
Ezogabine (Potiga)
Asthenia, dizziness, somnolence
Bladder flacidity, pigment changes nails, retina, lips
Perampanel (Fycompa)
Irritability, dizziness Mood change (SI or HI)
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Enrolling Drug Trials
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Enrolling Drug Trials
A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Intranasal Midazolam (USL261) in the Outpatient Treatment of Subjects with Seizure Clusters (P261-401) A Randomized, Double-Blind, Placebo-
Controlled Study of the Safety and Efficacy of Intranasal Midazolam (USL261) in the Outpatient Treatment of Subjects with Seizure Clusters (P261-401)
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Enrolling Drug Trials
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Dose-Response Trial of YKP3089 as Adjunctive Therapy in Subjects with Partial Onset Seizures with Optional Open-Label Extension (YKP3089 C017) The purpose of this study is to
determine the effective dose range of YKP3089.
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Enrolling Seizure Detection Study A Pivotal Phase III Trial of
Detecting Generalized Tonic-Clonic Seizures with a Seizure Detection and Warning System in Epilepsy Patients (Brain Sentinel) The purpose of this non-
interventional device study is to learn whether the experimental seizure detection device being studied (the Night WatchTM, an electromyography recorder and analyzer) is able to detect GTC seizures and alert caregivers when they start.
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Treatment options for Drug Resistant Epilepsy
14
Comprehensive Epilepsy Evaluation
VNS Therapy Diet• Ketogenic• Modified
Atkins• Low glycemic
index
Other• AEDs• Other
pharmacologics
Brain Surgery
• Resective surgery
– Corpus Callosotomy
– Hemispherectomy
– Multiple Subpial Transsections
• MR Laser Ablation
• Responsive Neurostimulation System (RNS)
VNSOV15-11-1000-WW
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Visualase
Minimally invasive
Heat ablation Developed in
tumor surgery Applied to
temporal lobectomy, lesional epilepsy surgery in children, ablation periventricular nodules
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Visualase: Mesial Temporal Lobe Epilepsy
• Median hospital stay of 1 day
• 77% patients with meaningful seizure reduction
• 67% patients seizure free
Willie et al., Neurosurgery, 2014.
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Visualase: Periventricular Nodular Heterotopias
Case report of 2 patients with excellent surgical outcomesEsquenazi et al., Epilepsy Research, 2014.
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Transorbital endoscopic amygdalohippocampectomy
Minimally invasive Advantage is that
cortex spared Procedure offered
only at Penn by Dr. Lucas
Transorbital endoscopic amygdalohippocampectomy: a feasibility investigation. Source:Journal of neurosurgery [0022-3085] Chen, H I yr:2014 vol:120 iss:6 pg:1428 -1436
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Vagus Nerve Stimulator
Broad spectrum Mechanism: unknown
– more later 55% responder rate
(reduction in sz by 50%)
Hoarseness, SOB, GERD
Evolving device to create trigger to tachycardia (85% focal epilepsy) to improve efficacy
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Seizure reduction improves over time and is sustained for at least 10 years post-VNS Therapy
20
6 month
s
1 Year 2 Years 4 Years 6 Years 8 years 10 Years
LVCF
35.7%
52.1%58.3% 60.4%
65.7%
75.5% 75.5% 76.3%
Mean
Seiz
ure
Red
ucti
on
• Seizure frequency was significantly reduced from baseline at each of the recorded intervals (P<0.01); N=65
Elliott RE, et al. Epilepsy & Behavior 20: 57-63, 2011VNSOV15-11-1000-WW
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NeuroPace® RNS® System Treatmentfor Epilepsy
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Indication for UseThe RNS® System is an adjunctive therapy in reducing the frequency of seizures in individuals 18 years of age or older with partial onset seizures who have undergone diagnostic testing that localized no more than 2 epileptogenic foci, are refractory to two or more antiepileptic medications, and currently have frequent and disabling seizures (motor partial seizures, complex partial seizures and/or secondarily generalized seizures). The RNS® System has demonstrated safety and effectiveness in patients who average 3 or more disabling seizures per month over the three most recent months (with no month with fewer than two seizures), and has not been evaluated in patients with less frequent seizures.
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The RNS System
Neurostimulatorand Leads
Patient Data Management System
(PDMS) Programmer
Remote Monitor
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RNS System: Responsive Stimulation
1. Physician identifies electrocorticographic activity to be detected
2. Detection settings specific to that activity are programmed
3. Stimulation is enabled using standard settings
4. Detection and stimulation is adjusted as needed
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RNS Clinical Trials
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2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
RNS System Clinical Studies
Feasibility Study65 implanted
Pivotal Study191 implanted
Long-term Treatment Study (230 enrolled)Long-term Treatment Study (230 enrolled)
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-3 -2 -1 0 1 2 3 4 5 6 26
RNS System Pivotal Study Design
Post-Op
StimOpt
Months Relative to Implant
Implant RandomizationSham Group: Stimulation On
Treatment Group: Stimulation On
Baseline Period
Open Label EvaluationBlinded
Evaluation
≈≈
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Subject DemographicsPivotal Study, N=191
Age at implant (years) 34.9 ±11.6
Gender (female) 48%
Duration of epilepsy (years) 20.5 + 11.6
Daily AEDs at enrollment 2.8 + 1.2
Seizures/28-days, mean (median; range) 34.2 (9.7; 3-338)
Prior VNS 34%
Evaluation with intracranial electrodes 59%
Prior epilepsy surgery 32%28
Data as of May 12, 2011
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Primary Effectiveness Endpoint
Post-op Month of Blinded Evaluation PeriodEntire Blinded Evaluation
Period
Month 4
Treatment
53 4 53
Sham
Treatment Sham
%Change in
Seizure Frequency
(GEE)
p = 0.012
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Pre-specified Subset Analyses Likelihood of good response
not different in patients Previously treated with VNS With mesial temporal v.
neocortical onsets With one or two seizure foci Having had a prior epilepsy
surgery
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Pivotal Study Responder RateAll subjects receiving stimulation
Sham
Treatment
Heck et al., 2014
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QOLIE-89 Group Improvements at Year 2
Mean change from baseline (T score)* Indicates significantly different from baseline at p<0.05
**
**
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Pivotal Study: SAEs First Post-Op Month (N=191)
Most common SAEs Implant site infection: 2.6% (5
subjects) Extradural hematoma: 1.0% (2
subjects) Hydrocephalus: 1.0% (2 subjects) Procedural headache: 1.0% (2
subjects)
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Neuropsychological and Mood Assessments
14 neuropsychological domains and 3 mood inventories
Testing at baseline, end of Blinded Evaluation Period and at 1 and 2 years post-implant No difference between Treatment and
Sham at end of Blinded Evaluation Period No deterioration in group scores at any
time point
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No Adverse Effects on MoodPivotal Study
Three inventories of mood1 administered at baseline, end of Blinded Evaluation Period and
at 1 and 2 years post-implant Beck Depression Inventory-II CES-D Profile of Mood States
No difference between Treatment and Sham at end of Blinded Evaluation Period
No deterioration at any time point in group scores
1 Summary scores from BDI-II, CES-D, POMS
Data as of May 12, 2011
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Year after Implanta
NbMedian % Reduction(1st and 3rd Quartile)
Responder Rate(95% CI)c
3 21460.0%
(24.2%, 85.8%)57.9%
(51.3%, 64.4%)
4 20463.3%
(29.8%, 91.2%)60.8%
(53.9%, 67.2%)
5 17265.5%
(23.2%, 91.2%)61.0%
(53.6%, 68.0%)
6 11565.7%
(30.6%, 87.1%)59.1%
(50.0%, 67.7%)A First 3 months b N represents subjects who have reached that time point in the ongoing study.c 95% confidence intervals (CI) calculated using the Wald method.
Data as of November 1, 2013
Long-term Seizure Reduction
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RNS® System: Longer Term Safety Data 256 patients treated over more than
1400 total implant years Rates of non-seizure related
hemorrhage (2.7%) and infection leading to explant (4.3%) comparable to DBS at 2 years1
Sustained improvements in QOL No adverse effects on cognition or
mood1 Weaver et al, JAMA 2009;301:63-73.
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The RNS System is a new type of adjunctive treatment for with intractable partial seizures
The RNS System is proven effective and safe in some patients who have failed medications
Patients who have been treated with the VNS or epilepsy surgery may respond to the RNS System
The RNS System provides an opportunity for improved seizure control with good tolerability and acceptable risk