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

Treatment of Seizures

Anti-seizureDrugs

Dis

ease

Mod

ifyin

gT

hera

pies

Diminish

Enhance

Key

Excitatory

Inhibitory

GabaergicAnticonvulsants

Anti-glutamatergic Anticonvulsants

Seizure NeuromodulationLesion/NetworkSurgery

Anticonvulsant Screening Program

Maximal ElectroShock Similar to ECT

Used to discover phenytoin

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

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

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

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

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

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)

Enrolling Drug Trials

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)

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.

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.

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

Visualase

Minimally invasive

Heat ablation Developed in

tumor surgery Applied to

temporal lobectomy, lesional epilepsy surgery in children, ablation periventricular nodules

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.

Visualase: Periventricular Nodular Heterotopias

Case report of 2 patients with excellent surgical outcomesEsquenazi et al., Epilepsy Research, 2014.

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

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

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

NeuroPace® RNS® System Treatmentfor Epilepsy

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.

The RNS System

Neurostimulatorand Leads

Patient Data Management System

(PDMS) Programmer

Remote Monitor

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

RNS Clinical Trials

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)

-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

≈≈

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

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

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

Pivotal Study Responder RateAll subjects receiving stimulation

Sham

Treatment

Heck et al., 2014

QOLIE-89 Group Improvements at Year 2

Mean change from baseline (T score)* Indicates significantly different from baseline at p<0.05

**

**

**

**

**

*

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)

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

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

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

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.

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