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1 Slide 1 Hot Topics in the World of Epilepsy Joseph I. Sirven, MD Professor and Chairman Department of Neurology 1 Slide 2 Surgery & Devices for Epilepsy Seizure Emergencies Cannabis What s Hot Slide 3 Thermal Ablation Patients with focal epilepsy where the focus is eloquent or with a high risk of surgical complications Lesional epilepsy Visualase system

Slide 4 Electrical Stimulation for Epilepsy Hypothalamus CM

Cerebellum Vagus CM=centromedian nucleus of thalamus Slide 5

Programmable cycles 40-50% responder rates Improve over time

-ko/holms VNS Slide 6 RNS RNS FDA Approved 11/2013 RNS

2 Slide 4 Electrical Stimulation for Epilepsy Hypothalamus CM Anterior thalamus Caudate Subthalamus Hippocampus Direct focus Cerebellum Vagus CM=centromedian nucleus of thalamus Slide 5 Vagal Nerve Stimulation/ ASPIRE System Implanted device Programmable cycles 40-50% responder rates Improve over time Well tolerated/qol Non-sedating Who is candidate?-ko/holms VNS Slide 6 RNS RNS FDA Approved 11/2013 RNS Restricted to Epilepsy Centers Detection/Therapy delivery 191 patients 39% seizure reduction Neurology 2011

$2 epileptogenic foci, refractory to two or more antiepileptic medications, frequent and disabling seizures (motor partial seizures, complex partial seizures and/or secondarily generalized seizures).$

3 Slide 7 Indication for Use Adjunctive therapy in reducing the frequency of seizures in individuals 18 years of age or older with: partial onset seizures diagnostic testing that localized no more than 2 epileptogenic foci, refractory to two or more antiepileptic medications, frequent and disabling seizures (motor partial seizures, complex partial seizures and/or secondarily generalized seizures).. Slide 8 Detects The RNS Neurostimulator Stores ECoG samples Provides responsive stimulation Slide 9 Combined Effectiveness and Safety: Interim Results of the Long-term Treatment Trial (N=256) Bergey et al. Neurology 2015

Slide 10 Long-term Seizure Reduction Year after Implant 1 (1 st and 3 rd Quartile) N 2 Median % Reduction Responder Rate (95% CI) 3 3 214 4 204 5 172 6 115 1 First 3 months of each year 60.0% (24.

4 Slide 10 Long-term Seizure Reduction Year after Implant 1 (1 st and 3 rd Quartile) N 2 Median % Reduction Responder Rate (95% CI) First 3 months of each year 60.0% (24.2%, 85.8%) 63.3% (29.8%, 91.2%) 65.5% (23.2%, 91.2%) 65.7% (30.6%, 87.1%) 2 N represents subjects who have reached that time point in the ongoing study. 3 95% confidence intervals (CI) calculated using the Wald method. 57.9% (51.3%, 64.4%) 60.8% (53.9%, 67.2%) 61.0% (53.6%, 68.0%) 59.1% (50.0%, 67.7%) Bergey et al., 2015 Data as of November 1, 2013 Slide 11 Serious AEs in 5.0% of 256 Subjects 1389 patient implant years, mean follow-up 5.4 years SAEs (Device related and not device related) % (#) Subjects Implant site infection 9.4% (24) a Complex partial seizures increased 7.8% (20) EEG monitoring b 7.2% (44) Therapeutic agent toxicity c 7.0% (18) Tonic-clonic seizures increased (more frequent) 5.9% (15) Medical device removal d 5.5% (14) a Infection rate 3% / neurostimulator procedure b Considered an SAE due to admission to an epilepsy monitoring unit. c Led to hospital admission in all 18 subjects; 16 due to an antiseizure medication toxicity. d Pursue other treatments (8), insufficient efficacy (4), subject elected (2). Bergey et al. Neurology 2015 Slide 12 DBS

5 Slide 13 Trigeminal Nerve Stimulation External device Approved by EU 30% responder rate Neurology 2013 Slide 14 Surgery & Devices for Epilepsy Seizure Emergencies Cannabis What s Hot Slide 15 When does a seizure become status? Isolated Seizures Seizure Clusters Status Epilepticus

$with general anesthesia Stage 4- >24 hours of anesthesia- Super Refractory Shorvon & Ferlisi 2011 Slide 17 Rossetti & Lowenstein, Lancet Neurology 10:922-930, 2011 Slide 18 Epilepsy Why is this$

6 Slide 16 Phases or Spectrum of Possibilities Stage 1- First 30 minutes Treat with benzodiazepines Stage minutes Treated with intravenous antiepileptic drug Stage 3- > 120 minutes Treated with general anesthesia Stage 4- >24 hours of anesthesia- Super Refractory Shorvon & Ferlisi 2011 Slide 17 Rossetti & Lowenstein, Lancet Neurology 10: , 2011 Slide 18 Epilepsy Why is this Hot?

7 Slide 19 New Delivery systems IM dosing IM midazolam vs IV Lorazepam ( N= 448) 10 mg Midazolam vs 4 mg IV lorazepam 73.4% vs 63.4% TTT 1.2 min vs 4.8 min TTSC 3.3 min vs. 1.6 min Others Diazepam autoinjector Time to next seizure 1.18 hr vs 2.7 hour placebo Rescue 55% placebo vs. 35.4% AI 3 products under investigation with midazolam Silbergleit NEJM 2/16/2012 Abou Khalil Epilepsy 11/2013 Slide 20 Immunopathology and Status Epilepticus Autoantibodies Associated with Paraneoplastic Seizures Cancer Other Neurologic Antibody Symptoms Anti-Hu (ANNA-1) Lung, Kidney, Neuropathy, ataxia, cognitive Breast, Prostate impairment, neuromuscular junction disorder, myelopathy, aphasia ANNA-2, Cervical, Lung, Bladder, Brainstem symptoms, spasticity, Ovarian extrapyramidal, autonomic dysfunction, cognitive impairment, ANNA-3 SCLC, esophagus Ataxia, neuropathy, autonomic dysfunction, brainstem symptoms, cognitive impairment, myelopathy Anti-Ta Testicular Cognitive impairment, ataxia, neuropathy, motor neuron disease Anti-Ma Breast, Parotid, Lung, Cognitive impairment, headache, Testicular brainstem symptoms, ataxia, extrapyramidal, dyssomnia Anti-CRMP5 SCLC, Thymoma Cognitive impairment, psychosis, extrapyramidal, ataxia, brainstem symptoms, neuropathy, autonomic dysfunction, neuromuscular junction disorder Voltage-gated potassium channel SCLC, Thymoma, Breast, Cognitive impairment, hallucinations, (VGKC) Hematologic dyssomnia, extrapyramidal, myoclonus, autonomic dysfunction, neuropathy N-Methyl-D-Aspartate (NMDA) Ovarian, Testicular, SCLC Psychiatric, extrapyramidal, autonomic Receptor dysfunction Glutamic Acid Decarboxylase SCLC, pancreatic, thymoma, Stiff-person syndrome, ataxia (GAD)-65 diabetes mellitus Slide 21 Surgery & Devices for Epilepsy Seizure Emergencies Cannabis What s Hot

species used by humans (China) >420 compounds: e.g.

8 Slide 22 Epilepsy Why is this Hot? Slide 23 Medical Marijuana Laws Slide 24 Cannabis sativa Cannabis sativa oldest known species used by humans (China) >420 compounds: e.g. Eugenol: acts at GABA A receptors 80 terpeno-phenol compounds, cannabinoids Sativa usually THC:CBD ratio v. indica. Sativa more psychic and stimulatory Compliments Orrin Devinsky, MD 24

Slide 25 Cannabis Indica Cannabis indica reference in Ancient Vedas text in India, ~ 1700 bce These strains are more sedative Orrin Devinsky, MD 25 Slide 26 Exogenous Cannabinoids Δ 9

9 Slide 25 Cannabis Indica Cannabis indica reference in Ancient Vedas text in India, ~ 1700 bce These strains are more sedative Orrin Devinsky, MD 25 Slide 26 Exogenous Cannabinoids Δ 9 Tetrahydrocannabinol (THC) Psychoactive CB1 agonist Cannabidiol (CBD) Non-psychoactive Very slight CB1/CB2 indirect antagonist; opposes some CNS effects of THC Antagonist at GPR55 receptor,? CBD receptor Slide 27 Four Controlled CBD Trials in Epilepsy STUDY INCLUSION PT # DOSE EFFICACY SAFETY CRITERIA TIME Notes Mechoul TLE/TRE 9 200/d x 3 5 Rx d: 2 Sz free, 1 No adverse am Groups not 4 CBD mos better, 1 events (1978) matched;? 5 PLA unchanged AEDs, no 4 Placebo: stats unchanged Cunha TLE/TRE >= CBD seizure Seizure-free: (1980) TCSz/wk 7 CBD mg/d free; 1 control 1 placebo DB? 8 PLA 3-18 wks seizure free 4 CBD Ames Residential/M mg/d x No group Mild (1985) R/TRE? CBD 4wks differences drowsiness -baseline data v PLA Trembly TRE adults 12 PLAC x 6 No group No data (1990) Conflict of 90?CBD v mos, CBD differences on paper and 92 PLA 300/dy x 6 seizures or cognbehavior tasks chapter mos Orrin Devinsky, MD

10 Slide 28 Survey of 19 Pediatric Epilepsy Patients on CBD>THC 19 children (2-16 years) used a CBDenriched medical marijuana 16 (84%) reduction in seizure frequency 2 were seizure free 8 (42%) >80% reduction in seizures 6 had a 25-60% reduction in seizures. (Porter & Jacobson, Epilepsy & Behavior, 2013) Slide 29 Survey of 19 Pediatric Epilepsy Patients on CBD-enriched Cannabis Benefits included improved alertness, mood, and sleep. Side effects: drowsiness and fatigue. Diagnoses: Dravet syndrome (13), Doose syndrome (4), Lennox Gastaut syndrome (1), and idiopathic epilepsy (1). (Porter & Jacobson, Epilepsy & Behavior, 2013) Slide 30 Epilepsy Why is this Hot?

Slide 31 Epidiolex (98% CBD) Studies NYU enrolled 25 children and young adults with TRE Dravet, LGS, Focal epilepsy, CDKL4, etc Orphan drug indication approved by FDA for Dravet and LGS plans for RCT

11 Slide 31 Epidiolex (98% CBD) Studies NYU enrolled 25 children and young adults with TRE Dravet, LGS, Focal epilepsy, CDKL4, etc Orphan drug indication approved by FDA for Dravet and LGS plans for RCT Orrin Devinsky, MD Slide 32 Background and Introduction Expanded access INDs granted by FDA to individual pediatric epileptologists In response to unmet medical need In children and young adults with range of drug-resistant epilepsies FDA authorization received to date for approx. 400 children at 17 US hospital sites Significant body of data being generated Patients treated according to standardized treatment plan All seizure types Use of concomitant meds, blood levels Adverse events Orrin Devinsky, MD July 2015 Slide 33 Latest Data: Overview Treatment-resistant children and young adults (mean age 11 years) Epidiolex added to existing meds. Patients on average 3 other AEDs Patients include extreme and rare forms of epilepsy including several patients with major congenital structural brain abnormalities Data presented for all 58 patients with at least 12 weeks continuous exposure UCSF: 9 patients: NYU: 26 patients; Boston: 23 patients 16 week data presented for all 40 patients with 16 week data Total safety database of 151 patients Total estimated exposure: 50 patient-years Orrin Devinsky, MD July 2015

12 % of Patients % Seizure Reduction % of Patients Slide 34 All Patients (n=58) All Seizures - Responder Analysis 60% 50% 40% Patients with at least: 50% Responders 70% Responders 90% Responders Seizure Free 41% 48% 43% 55% 40% 30% 20% 10% 0% Weeks 41-4 Weeks 85-8 Weeks 9-12 Weeks Wk 12 WK Aggregate Av (n=58) (n=40) 34 Total Seizures = Convulsive and Non-Convulsive Slide 35 Dravet Syndrome Patients (n=12) Median % Reduction in Convulsive Seizures 0% -10% -20% Weeks 41-4 Weeks Week Weeks 9-12 Weeks Week Wk12 Aggregate WK Av -30% -40% -50% -60% -70% -80% -72% -62% -51% (n=12) -56% (n=9) -56% Orrin Dervinsky, MD 15 July 2015 Slide 36 Dravet Syndrome Patients (n=12) Convulsive Seizures - Responder Analysis Patients with at least: 80% 70% 60% 50% Responders 70% Responders 90% Responders Seizure Free 58% 67% 58% 56% 58% 50% 40% 30% 20% 10% 0% Weeks Weeks Weeks Weeks Wk Aggregate 5 (n=12) (n=9) 15 July 2015 Orrin Devinsky, MD 36

13 % of Patients % Seizure Reduction Slide 37 All Patients with Atonic ( Drop ) Seizures (n=12) Median % Reduction in Atonic Seizures 0% -10% -20% Weeks 41-4 Weeks Weeks 9-12 Weeks Wk12 Aggregate WK Av -30% -40% -50% -60% -70% -80% -57% -62% -52% (n=12) -76% (n=10) -52% Orrin Devinsjy, MD 15 July 2015 Slide 38 All Patients with Atonic ( Drop ) Seizures (n=12) Atonic Seizures - Responder Analysis 80% 70% 60% 50% 40% 30% Patients with at least: 50% Responders 70% Responders 90% Responders Seizure Free 58% 67% 58% 70% 50% 20% 10% 0% Weeks Weeks 85-8 Weeks Weeks Week Wk 12 Aggregate WK Av (n=12) (n=10) Orrin Devinsky, MD 15 July 2015 Slide 39 Safety Data (151 patients, approx. 50 patient years treatment) Most common AEs all causes (10% or more of patients) - Somnolence 19% - Fatigue 11% Other AE s in 5% or more of patients are diarrhoea, decreased appetite, convulsion 2 withdrawal due to AEs Allergy to sesame oil 5 withdrawals due to lack of clinical effect Serious AEs reported in 26 patients (incl 2 deaths due to SUDEP). None deemed related to Epidiolex Orrin Devinsky, MD

Slide 40 Conclusions New data on additional patients is consistent with previous data on initial 27 patients Epidiolex treatment is associated with a meaningful reduction in seizure frequency in a

14 Slide 40 Conclusions New data on additional patients is consistent with previous data on initial 27 patients Epidiolex treatment is associated with a meaningful reduction in seizure frequency in a high proportion of patients with otherwise drug-resistant epilepsy The response seen in the first month of treatment is maintained (and possibly increased) with increasing duration of treatment Seizure freedom is seen in a portion of responders Patients with Dravet syndrome have shown an encouraging response Epidiolex treatment is associated with a reduction in drop seizures, the seizure type considered for primary efficacy in LGS trials Few patients withdrawing from treatment due to side effects or lack of clinical effect Orrin Devinsky, MD July 2015 Slide 41 Conclusions Data from methodologically limited clinical trials of CBD, parental reports of CBD-enriched medical marijuana and animal studies suggest that CBD may have valuable anti-seizure properties and the benefit:risk ratio may be favorable. Randomized, placebo-controlled clinical trials are underway Orrin Devinsky, MD Slide 42

Cannabidiols & Epilepsy. Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine

Cannabidiols & Epilepsy. Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine Cannabidiols & Epilepsy Orrin Devinsky, M.D. Department of Neurology NYU Langone School of Medicine Cannibas in History Cannibas sativa? ~8,000 bce in China - rope Cultivated, used for garments, bowstrings,