Current Research/New Treatments In Adult Epilepsy Philippe Douyon, MD

Aim of Treatment of Epilepsy In Ancient Time “But if the mischief lurked there until it strike root, it will not yield either to the physician or the changes of age, so as to take its departure, but lives with the patient until death.” The great importance to treat the patient before the disease had become chronic Best prognosis – when the attacks started from the hands and feet, patient were young, not mentally impaired, or suffers of apoplexy. “If epilepsy appeared in old people they were best helped if left alone

Aim of Treatment of Epilepsy In Ancient Time 1st and most important treatment: PREVENTION “For it is easier to prevent what is threatening than to expel what is present” Epileptics – tried to prevent the development of an attack when they felt its onset Using remedies Remove whatever was thought to be the offending agent If the seizure started in one extremity, they would pull at the part, have it bound and stretched to chase the attack away

Epilepsy In Ancient Medical Science Treatments Complete abstinence from food and drink Purging of the Phlegm Use of diuretics Walking and exercise Phlebotomy

Aim of Treatment of Epilepsy In Ancient Times If the person who sees the spasm, first urinates in his shoe, tips it back and forth and then gives the patient the urine to drink, the seizure will stop immediately. Antonius Guainerius, 1440

Aim of Treatment of Epilepsy In Ancient Times Trephining – in order to give an outlet to the materia peccans. “The last remedy….but by this means times desperate epilepsies have been cured.

The Ideal Medicine For Epilepsy Effective Safe Few side effects Easily absorbed Few daily doses No drug interactions Inexpensive NONE EXISTS

Choice of AEDs Based on Seizure type/epilepsy syndrome Co-morbidities Weight, other medical conditions (e.g: hepatic or renal disease), other medications The most effective Rx is with a single drug, chosen on the basis of epilepsy syndrome (and type of seizure) and titrated to the seizure control or side effects Problems with polytherapy Additive side effects Drug interactions 8

Antiseizure Medications DATE INTRODUCED OR PLANNED FOR INTRODUCTION IN THE USA Clobazam ganaxolone harkoseride loreclezole Losigamone lacosamide perampanel pregabalin retigabine/ ezogabine rufinamide stiripentol vigabatrin others valproate carbamazepine diazepam felbamate gabapentin lamotrigine tiagabine topiramate oxcarbazepine levetiracetam zonisamide ethosuximide primidone phenytoin phenobarbital (bromide) 1850 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

Acute (rescue) Management of Seizures

Abortive Agents – Overview Benzodiazepines – cornerstone of the emergent phase of treatment of seizures/status epilepticus. Efficacy of IV Lorazepam was established by 3 independent Trials “Prehospital status epilepticus treatment trial” Sz activity was controlled in 60% of cases by 2-4mg of lorazepam versus 40% with 5-10mg of diazepam and 20% of placebo Trial comparing lorazepam to IV diazepam plus phenytoin or IV phenytoin or IV phenobarbital Lorazepam resulted in the control of status epilepticus in 65% of cases Rapid Anticonvulsant Medication Prior to Arrival Trial (RAM-PART): IM midazolam was superior to IV lorazepam in controlling generalized convulsive status epilepticus (73% versus 63%) when administered en route by paramedics.

Abortive Agents – Overview Benzodiazepines These trials indicate: If IV access is available, IV Lorazepam is the treatment of choice If IV access is not available, IM Midazolam can be used Intranasal or buccal administration of midazolam or rectal administration of diazepam are appropriate and safe possibilities

Abortive Agents – Overview Benzodiazepines for a prolonged seizure Mechanism of action of benzodiazepines Binds to GABA receptor and reduces the excessive excitation in the brain Administration routes Oral, intravenous, intramuscular, rectal, intranasal, buccal

Abortive Agents – Overview Commercially available formulations at outpatient setting Diazepam – rectal gel Clonazepam – tablet (wafer, disintegrating tablet [ODT]) Conditionally available formulations at outpatient setting Midazolam – intranasal or buccal May be available at compounding pharmacy Need a special devise to make mist (atomizer) for intranasal formulation

Diazepam Rectal gel 20 mg (for 12.5 mg, 15 mg, 17.5 mg, and 20 mg) 10 mg (for 5 mg, 7.5 mg, and 10 mg) 16

IN midazolam Gerrit-Jan de Haan et al. (2010) Study population Dose Primary outcome: comparisons between diazepam (rectal) and midazolam (intranasal) in efficacy, safety, and preference Study population Adults (N = 21) Male: 13 (61.9%) Dose Diazepam (DZP): 10 mg Midazolam (MDZ): 2.5 mg 17

IN midazolam Gerrit-Jan de Haan et al. (2010) Results Success rate DZP 89% vs. MDZ 82% (NS) Time to stop seizures: NS ADRs No severe ADRs were observed More CNS ADRs in DZP group; more local irritation in MDZ group Preference (easy to use) MDZ > DZP (p<0.001)

Summary Three benzodiazepine drugs have been used to stop prolonged seizures at outpatient setting Each benzodiazepine and its formulation are different in pharmacokinetics and caregiver’s preference Select appropriate rescue medicine in accordance with patient’s needs, such as social factors (e.g., patient’s or caregiver’s preference)

Suggested Rational Use: What abortive agent would you recommend for this situation? Diazepam rectal Appropriate for younger children when a seizure lasts three to five minutes What if the patient has multiple seizures within a short period (cluster)? Clonazepam ODT Appropriate for clusters of seizures What if he is a teenager? Intranasal midazolam Appropriate for older children May become the drug of choice for all rescue Exception: short half-life may not help with clusters

Chronic Treatment of Epilepsy Anti-seizure medications

Brivaracetam (Rikelta) Brivaracetam – an analog of Levetiracetam (Keppra) Investigational drug for the treatment of partial onset seizures Currently in Phase III clinical trial to assess the efficacy and safety as adjunctive treatment for partial onset

Brivaracetam – structurally similar to keppra; but also has a similar mechanism of action

AED Mechanisms of Action Brivaracteam – works at the level of the synaptic vesicles, like Keppra, but also has sodium blocking activity. Higher affinity than Keppra for synaptic vesicles Brivaracetam was much stronger in animal models. 10x more potent for the prevention of seizures in mouse models Levetiracetam (Keppra) causes irritability/depression in some patients Unknown if Brivaracetam will have improved tolerability profile

Brivaracetam Trials Phase III Study Statistically significant reductions in partial onset seizures per 28 day period 22.8% for Brivaracetam 100mg/daily 23.2% for Brivaracetam 200mg/daily 50% responder rate for Brivaracetam 100 and 200mg/daily were 38.9% and 37.8% compared with 21.6% for placebo. Most frequent emergent adverse events were headahce, somnolence, dizziness, and fatigue.

Brivaracetam Brivaracetam: Pending regulatory filings and approval, brivaracetam would provide new option for adult epilepsy patients with partial onset seizures as an add-on therapy. Other uses (i.e., generalized seizures or monotherapy) will be explored at a later time.

Eslicarbazepine

Reasons for exit ESL 1,200mg (n=60) ESL 1,600 (n=118) Total (n=178) One episode of status epilepsy 23 17 40 Secondarily generalized (atypical) 1 2 fold increase in sz from baseline in 28 days 6 5 11 2 fold increase from baseline in 2 consecutive days Worsening seizures or increase sz 8 4 12

Influence of AEDs during baseline period

Influence of AEDs during baseline period

Exit Rates for ESL 1,600 and 1,200 versus Historical Control (65.3%)

Eslicarbazepine (Aptiom): ESL was efficacious and well tolerated as monotherapy It led to a reduction in seizure frequency Exit rate for ESL 1,600 and 1,200mg daily doses were superior to historical controls Difference in exit rates between doses was not statistically significant

Ganaxolone Synthetic analog of allopregnanolone No progestational activity Positive allosteric modulator of GABAA Receptor Protective in diverse rodent seizure modes

Ganaxolone Phase 2b: Multi-Center, Double-Blind, Randomized, Placebo-Controlled Trial-Adjunctive Rx for Adults with Drug Resistant Partial-onset Seizures. 67 weeks: 4 weeks baseline, 9 week DB placebo-controlled phase, 52 week open label Main Selection Criteria: 18 or older, 3 or more POS, AEDs 1-3 NEREG was first to enroll in this global study!

Acute and sustained efficacy in adults with partial onset seizures RNS® System First of a kind device to provide targeted responsive stimulation for epilepsy Acute and sustained efficacy in adults with partial onset seizures Stimulation well tolerated; risks of implant procedure comparable to similar procedures Provides another treatment option for adults with medically intractable partial onset seizures

The RNS® Neurostimulator: Main Functions Detection ECoG storage Responsive stimulation

Management System (PDMS) Neurostimulator and Leads The RNS System Patient Data Management System (PDMS) Neurostimulator and Leads Programmer Remote Monitor

Clinician Sets-up Detection

Neurostimulator stores ~6 minutes of ECoG ECoG Storage Neurostimulator stores ~6 minutes of ECoG The number of ECoGs stored is determined by The number of ECoG channels The duration of each ECoG segment Once memory is full, oldest stored ECoGs replaced by newly stored ECoGs Patients asked to upload neurostimulator data to PDMS daily and after seizures

Clinician Selects ECoGs to be Stored The clinician programs the neurostimulator to store specific types of ECoGs Most common triggers for ECoG storage are Magnet swipe by the patient Changes in the ECoG suggestive of electrographic seizures

ECoG Storage Triggered by Magnet Swipe

Physician identifies electrocorticographic activity to be detected Detection settings specific to that activity are programmed Stimulation is enabled using standard settings Detection and stimulation is adjusted as needed

Histogram of Detections and Stimulations Month by Day Day by Hour Detections Stimulations

Clinician Selects Stimulation Pathway Stimulation delivered to any combination of 8 electrodes and the neurostimulator case – + – + + ̶ + ̶ ̶ + ̶ +

Feasibility Study Pivotal Study 65 implanted Pivotal Study 191 implanted Long-term Treatment Study (230 enrolled) Long-term Treatment Study (230 enrolled) 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

Pre-specified Subset Analyses Likelihood of good responses is not different in patients who: Previously treated with VNS Mesial temporal versus neocortical onsets One or two seizure foci Having had a prior epilepsy surgery

Pivotal Study Primary Safety Endpoint Met (Device-Related and Not Related) Period SAE Rate1 RNS System Comparator % subjects [upper 95% CI] Acute: Implant – 4 weeks Pre-specified comparator: Intracranial electrodes + epilepsy surgery 12.0% [16.5%] 15% [20%] Short-term Chronic: Implant – 12 weeks Pre-specified comparator: DBS for movement disorders 18.3% [23.4%] 36% [42%]

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)

Long-term Seizure Reduction Year after Implant1 N2 Median % Reduction (1st and 3rd Quartile) Responder Rate (95% CI)3 3 214 60.0% (24.2%, 85.8%) 57.9% (51.3%, 64.4%) 4 204 63.3% (29.8%, 91.2%) 60.8% (53.9%, 67.2%) 5 172 65.5% (23.2%, 91.2%) 61.0% (53.6%, 68.0%) 6 115 65.7% (30.6%, 87.1%) 59.1% (50.0%, 67.7%) 1 First 3 months 2 N represents subjects who have reached that time point in the ongoing study. 3 95% confidence intervals (CI) calculated using the Wald method.

Seizure Free Periods: All Studies

Related to the Implanted Device % (#) subjects with SAE SAEs Affecting ≥ 2.5% of Subjects (N=256) All Studies, Median F/U 5.7 years; 1199 patient implant years Related to the Implanted Device % (#) subjects with SAE Implant site infection1 7.4% (19) Medical device removal 3.9% (11) Premature battery depletion2 4.6% (12) Device lead damage 3.5% (9) Device lead revision 2.7% (7) 1 All soft tissue infections 2 First of 3 battery manufacturers

Epilepsy Surgery When do we consider “traditional” epilepsy surgery? Focal/Partial Epilepsy Medically intractable epilepsy Failure of ???Intolerable adverse effects to AEDs

Visualase Laser Treatment Evaluation is same as for epilepsy surgery No need for open brain operation Visualase is a new miminally invasive form of epilepsy surgery utilizing laser therapy. This is under study at our site. Our study is called A Study to Prospectively Evaluate the Effects of MR-guided Laser Ablation of Epileptogenic Foci in Patients with Treatment Resistant Partial Epilepsy 61

Visualase Probe inserted in OR Transferred to MRI Laser Treatment Implant Probe inserted in OR Transferred to MRI Treatment Laser Treatment MRI monitors safety of Laser Rx real-time Follow up Probe Removed Patient can leave same day The advantage of visualase is that we can avoid a large open brain surgery. The surgery instead uses a probe like a biopsy. Here is how the procedure goes: 62

Summary