Epilepsy Treatment Update for Patients Suffering From Seizure Clusters Tuesday, December 3, 2019 National Harbor, MD US-P-NZ-SC-1900152 12/19 ! Disclaimer • The speaker today is being compensated by UCB, the sponsor of this presentation • The use of products in any way other than that specified by the FDA approved US Prescribing Information is off-label and cannot be recommended by UCB • Disclosures: research grants from Lundbeck, Eisai; advisory boards and consulting for Abbot, Alliance, Aquestive, Eisai, Lundbeck, SK Life Sciences, UCB Pharma; speaker bureau for Aquestive, Eisai, Sunovion, UCB Pharma 2 What Is a Seizure Cluster? • Seizure clusters can be broadly Various Alternative Names for Seizure Clusters5 defined as acute episodes of Acute consecutive seizures that occur with Recurrent Flurries Repetitive Seizures short interictal periods and may be Seizures distinguishable from a patient’s typical seizure pattern or frequency1-4 • No consensus definition of seizure Cyclical Crescendo Serial clusters currently exists1 Seizures Seizures Seizures Sources: 1. Haut SR. Curr Opin Neurol. 2015;28:143-150. 2. Mitchell WG. Epilepsia. 2996;37:S74-S80. 3. Haut SR. Epilepsy Behav. 2006;8:50-55. 4. Dreifuss FE, et al. N Engl J Med. 1998;338:1869-1875. 5 5. Jafarpour S, et al. Seizure. 2019;68:9-15. Burden of Seizure Clusters Impact of Seizure Clusters on Patients’ and Their Caregivers’ Lives Percent of Respondents, % Patients (N=259) Caregivers (N=263) Driving Driving 69% Extracurricular Extracurricular Overall mood Overall mood activities 69% activities 58% 55% 41% 10% 52% 48% 59% 69% Travel Work Travel 34% Work 67% Independence Independence Seizure clusters represent substantial burdens to patients’ their caregivers’ lives Source: Penovich PE, et al. Neurologist. 2017;22:207-214. 6 Gaps in Communication About Seizure Clusters Healthcare Professional Community Member • 12-hour period for children • Can range from daily to once a year Time frame • 24-hour period for adults • Over a relatively short period of time, usually Duration • Ranges from a few days to a few weeks less than 24 hours Frequency • Multiple seizures, usually 3 or more • No specific number of seizures Note: Based on qualitative reviews and analyses of the medical literature (Healthcare Professional) and of the Epilepsy Foundation website (Community Member). This theme refers to the understanding or the definition of seizure clusters as understood by healthcare professionals or epilepsy community members. Source: Buelow JM, et al. Epilepsy Behav. 2016;57:16-22. 7 Average Seizure Cluster Duration Compared With Isolated Seizures Seizure Duration Based on Position Within a Cluster Compared With Isolated (Non-Cluster) Seizuresa Mean (SD) Seizure Duration, Seconds Intracluster vs Terminal Seizure Cluster Mean Number of Seizure Duration Definition Seizures/Cluster Intracluster Terminal Isolated Seizures Seizures Seizures P Valueb 2 or more seizures 2.8 71 (78) 84 (68) 90 (92) 0.014 within 2 hours 2 or more seizures 3.2 78 (72) 95 (98) 86 (92) 0.011 within 4 hours 2 or more seizures 3.8 82 (81) 83 (69) 91 (108) 0.294 within 8 hours a Data based on EEG findings from 996 seizures among 92 patients. b There were no statistically significant differences between mean terminal seizure duration and mean isolated seizure duration. Abbreviations: EEG, electroencephalogram. 8 Source: Ferastraoaru V, et al. Epilepsia. 2016;57:889-895. Seizure Clusters May Involve the Failure of Inhibitory Mechanisms Mechanisms Reported to Be Involved in Seizure Termination1 Seizure onset zone Substantia nigra pars reticulata Single Neurons Local Network of Neurons Remote Brain Regions Transmembrane ion gradients Gap junction decoupling GABAergic synaptic inhibition Energy failure (eg, ATP or glucose loss) Changes in neuromodulator levels GABAergic synaptic inhibition Binding of benzodiazepines to the GABA receptor is believed to potentiate GABAergic inhibition2 Abbreviations: ATP, adenosine triphosphate; GABA, γ-aminobutyric acid. 9 Sources: 1. Lado FA, Moshé SL. Epilepsia. 2008;49:1651-1664. 2. Riss J, et al. Acta Neurol Scand. 2008;118:69-86. Seizure Clusters and Hospitalizations Seizure-Related Hospitalizations Among Patients With Epilepsy (non-SE) Patients, % 0% 25% 50% 75% 100% Seizure clustering 73% (N=41) P=0.006 Nonclustering 59% (N=100) Note: Seizure cluster defined as 3 or more seizures in 24-hour period. Abbreviation: SE, status epilepticus. 10 Source: Haut SR, et al. Epilepsia. 2005;46:146-149. Seizure Clusters and Status Epilepticus History of Convulsive Status Epilepticus Among Patients With and Without Seizure Clusters 100% Seizure clustering Nonclustering 75% P=0.03 P <0.002 50% 44% 39% Patients, % Patients, 25% 12% 13% 16/41 12/100 16/36 5/40 0% Haut SR, et al (2005)1 Haut SR, et al (1999)2 Note: Seizure clusters defined as 3 or more seizures over 24-hour period in both studies. Sources: 1. Haut SR, et al. Epilepsia. 2005;46:146-149. 2. Haut SR, et al. Epilepsia. 1999;40:1832-1834. 11 Seizure Clusters and Mortality Survival With and Without Seizure Clusters 100 – , % 90 – 80 – urviving 70 – Patients with seizure clusters have a S 60 – ~3.5-fold greater risk of death* 50 – 40 – compared to patients without clusters 30 – *95% CI, 1.25-9.78 20 – No Seizure Clusters (N=94) 10 – Seizure Clusters During Treatment (N=12) Cumulative Proportion Proportion Cumulative 0 – 0 5 10 15 20 25 30 35 40 45 Years After Onset of Epilepsy Abbreviation: CI, confidence interval. 12 Source: Sillanpää M, Schmidt D. Brain. 2008;131:938-944. Risk Factors for Experiencing Seizure Clusters Prevalence of Select Risk Factors Among Patients Aged 16 Years or Older With and Without Seizure Clusters Patients With Risk Factor, % Risk Factor 0% 25% 50% 75% 100% History of… 70.6% Complex partial seizure 48.5% 51.0% Simple partial seizure 43.4% 15.4% Status epilepticus 5.8% Febrile seizures 10.5% 7.9% 10.5% Nocturnal seizure 7.1% 8.7% Tonic seizure 2.0% 7.8% Drop seizure 1.9% Note: All P values <0.05 based on a univariate analysis. Psychogenic nonepileptic seizure 4.7% 2.5% Lennox-Gastaut Syndrome 2.3% Patients with clusters (N=612) 0.9% Patients without clusters (N=3504) Note: Data from a retrospective univariate analysis. Seizure clusters are associated with multiple seizure types Source: Chen B, et al. Epilepsy Res. 2017;133:98-102. 13 Seizure Emergency Action Plans In a survey of 259 patients with epilepsy… Clinician Recommendations and Patient Responses to Seizure Clusters -100%Patients (N=259),-50% % 0% Clinicians50% (N=339),100% % 30% 20% 79% Have a seizure Rescue medication emergency plan Call doctor's office 20% 67% Visit ER 24% 61% Stay calm 34% 50% Extra/increased dose of AED 11% 28% VNS 10% 21% 70% Visit urgent care 7% 12% Do not have a Other 5% 2% seizure emergency plan PatientPatients Typically nothing 27% 1% PhysicianClinicians Most patients with seizure clusters report that they do not have a seizure emergency plan Abbreviations: AED, antiepileptic drug; ER, emergency room, VNS, vagus nerve stimulator. 14 Source: Penovich PE, et al. Neurologist. 2017;22:207-214. Use of Various Benzodiazepines as Rescue Medication Prescriptions for Rescue Medications Among Rescue Medication Use for Patients With Seizure Clusters (N=612) Patients With Seizure Clusters (N=612) 2.1% 40% 10.8% 3+ prescriptions 2 prescriptions 30% 28.9% 20% 30.6% % Patients, 1 prescription 10% 7.8% 7.0% 6.9% 56.5% 5.4% No prescription n=177 n=48 n=43 n=42 n=33 0% Lorazepam Diazepam Diazepam Midazolam Clonazepam (oral) (rectal) (oral) (intranasal) (oral) Less than half (43.5%) of patients who experienced seizure clusters had a prescription for a rescue medication Source: Chen B, et al. Epilepsy Res. 2017;133:98-102. 15 Pharmacokinetics of Benzodiazepines a Tmax (hours) Elimination Half-life (hours) 0 1 2 3 4 5 6 7 8 9 10 11 12 Clorazepate (IM) 2.7-11b >24 Clorazepate (PO) 0.5-2b Clonazepam (PO) 1-4 19-60 Clobazam (PO) 1.3-1.7 10-30 Diazepam (PO) 0.5-1.5 Diazepam (IM) 0.5-1.0 21-70 Diazepam (R) 0.17-0.75 Midazolam (PO) 0.5-0.97 Midazolam (IM) 0.24-0.51 1-4 c Midazolam (IN) 0.15-0.32 Lorazepam (PO) 2.4 Lorazepam (SL) 2.3 7-26 Lorazepam (IM) 1.2 a In healthy subjects. b Tmax for N-desmethyldiazepam after administration of clorazepate. c Compounded intranasal midazolam.2 Abbreviations: IM, intramuscular; IN, intranasal; PO, oral; R, rectal; SL, sublingual. 16 Sources: 1. Riss J, et al. Acta Neurol Scand. 2008;118:69-86. 2. Knoester PD, et al. Br J Clin Pharmacol. 2002;53:501-507. NAYZILAM® (midazolam) nasal spray, CIV Product Overview Please see Important Safety Information, including the Boxed Warning for concomitant use with opioids, included in this presentation. Please refer to full Prescribing Information provided by the UCB Representative and visit www.NAYZILAM.com NAYZILAM® is a registered trademark of the UCB Group of Companies. All other trademarks are the property of their respective owners. ©2019 UCB, Inc., Smyrna, GA 30080. All rights reserved. 17 US-P-NZ-SC-1900152 12/19 NAYZILAM® Is the First and Only Nasal Spray Indicated to Treat Seizure Clusters NAYZILAM is a benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 12 years of age and older. WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.1), Drug Interactions (7.2)]. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.