Epilepsy Treatment Update for Patients Suffering from Seizure Clusters

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.  Limit dosages and durations to the minimum required.  Follow patients for signs and symptoms of respiratory depression and sedation.

Please see additional Important Safety Information within this presentation. Source: NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc. Please refer to full Prescribing Information provided by the UCB Representative and visit www.NAYZILAM.com.

18 ® NAYZILAM Is Now Available Single-use nasal spray supplied in boxes of 2 blister pack units

NAYZILAM is a midazolam formulation designed for nasal delivery

NAYZILAM can be administered by a non–healthcare professional Image is for illustrative purposes only.

NAYZILAM is contraindicated in patients with acute narrow-angle glaucoma. Concomitant use of benzodiazepines, including NAYZILAM, and opioids may result in profound sedation, respiratory depression, coma, and death. NAYZILAM may cause increased CNS-depressant effect when used with alcohol or other CNS depressants. Concomitant use with moderate or strong CYP3A4 inhibitors may result in prolonged sedation due to a decrease in plasma clearance of midazolam. Antiepileptic drugs, including NAYZILAM, increase the risk of suicidal ideation and behavior. Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours.

Source: NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc.

Key Pharmacokinetic Parameters Mean Plasma Concentration After 2 Doses of Intranasal Midazolam in Healthy Adults1 Administered 10 Minutes Apart in Patients With Epilepsy2,a,b

Absorption

• Median Tmax 17.3 minutes Detected in plasma by 5 minutes post dose • Mean absolute bioavailability ~44%

Distribution ) mL • Total volume of distribution ~226.5 L

• ~97% protein bound SD) NAYZILAM Plasma NAYZILAM SD)

Metabolism ± Concentration (ng/ Concentration • Primarily liver and intestinal CYP3A4 ( Mean Elimination Hours Post Dose • Half-life 2.1 hours to 6.2 hours aMean plasma concentration was estimated from the Pharmacokinetic Analysis Population: All subjects who received both test doses in the ARTEMIS I clinical trial, with sufficient plasma concentration data to accurately estimate pharmacokinetic parameters (n=235).2 bThe formulation of intranasal midazolam used in this study was different from the final formulation of NAYZILAM. Sources: 1. NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc. 2. Data on file. UCB Inc.

CONTRAINDICATIONS NAYZILAM is contraindicated in patients with acute narrow-angle glaucoma.

RISKS FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of benzodiazepines, including NAYZILAM, and opioids may result in profound sedation, respiratory depression, coma, and death. • Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. • Limit dosages and durations to the minimum required. • Follow patients for signs and symptoms of respiratory depression and sedation.

RISKS OF CARDIORESPIRATORY ADVERSE REACTIONS Serious cardiorespiratory adverse reactions have occurred after administration of midazolam. Warn patients and caregivers about the risks of respiratory depression, cardiac, and respiratory arrest. Respiratory depression was observed with the administration of NAYZILAM during clinical trials. Cardiac or respiratory arrest caused by NAYZILAM was not reported during clinical trials.

Source: NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc.

CENTRAL NERVOUS SYSTEM DEPRESSION FROM CONCOMITANT USE WITH OTHER CENTRAL NERVOUS SYSTEM DEPRESSANTS, OR MODERATE OR STRONG CYP3A4 INHIBITORS Drug products containing midazolam, including NAYZILAM, have a central nervous system (CNS) depressant effect.

Risks from Concomitant Use with Other CNS Depressants NAYZILAM may cause an increased CNS-depressant effect when used with alcohol or other CNS depressants (eg, opioids). Warn patients and caregivers that the use of NAYZILAM in combination with alcohol or other CNS depressant drugs may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

Risks from Concomitant Use with Moderate or Strong CYP3A4 Inhibitors Concomitant use of NAYZILAM with moderate or strong CYP3A4 enzyme inhibitors may result in prolonged sedation because of a decrease in plasma clearance of midazolam. Caution patients against engaging in hazardous occupations requiring mental alertness, such as operating machinery, driving a motor vehicle or riding a bicycle until they have completely returned to their level of baseline functioning.

Source: NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc.

SUICIDAL BEHAVIOR AND IDEATION Antiepileptic drugs (AEDs), including NAYZILAM, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with NAYZILAM for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Advise patients and caregivers to be alert for these behavioral changes and to immediately report them to the healthcare provider.

IMPAIRED COGNITIVE FUNCTION Midazolam, including NAYZILAM, is associated with a high incidence of partial or complete impairment of recall for several hours following an administered dose. Counsel patients on when they can engage in activities requiring complete mental alertness, operate hazardous machinery, or drive a motor vehicle after taking NAYZILAM.

GLAUCOMA Benzodiazepines, including NAYZILAM, can increase intraocular pressure in patients with glaucoma. NAYZILAM may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. NAYZILAM is contraindicated in patients with narrow-angle glaucoma.

Source: NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc.

ADVERSE REACTIONS In the randomized, double-blind, placebo-controlled trial, the most common adverse reactions (≥5% in any NAYZILAM treatment group) were somnolence, headache, nasal discomfort, throat irritation, and rhinorrhea.

NAYZILAM is a Schedule IV controlled substance.

Source: NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc.

ARTEMIS I Study Design: Comparative Phase1,2

1st 2nd Dose Dose

5 mg NAYZILAM (double-blind) n=134 If seizure cluster did not stop within 10 minutes Treatment Groups Or another seizure 5 mg NAYZILAM Randomized 2:1 occurred within 6 hours (open-label) Placebo And no sign of (double-blind) respiratory depressiona n=67

• Tolerability was assessed in the Test Phase in which 292 patients received two 5 mg doses of NAYZILAM separated by 10 minutes in the absence of a seizure: patients who met predefined criteria continued on to the Comparative Phase2 aThe patient did not have <8 breaths per minute, require emergency rescue treatment and assisted breathing or intubation, or have excessive sedation.1 Sources: 1. Detyniecki K, et al. Epilepsia. 2019;60:1797-1808. 2. NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc.

Primary Endpoint1 Key Secondary and Exploratory Endpoints1

Treatment success with second dose No recurrence of seizures (open‐label) within 6 hours of initial blinded study drug dose Time to next seizure occurring Treatment >10 minutes after drug administration Success = + Return to baseline functionality within Seizure termination within 24 hours of drug administrationa 10 minutes after initial blinded study drug dose

aReturn to baseline functionality: time when subject was able to return to what he/she was doing prior to the seizure cluster.2 Sources: 1. Detyniecki K, et al. Epilepsia. 2019;60:1797-1808. 2. Data on File. UCB Inc.

Patient Population Size1 Number of AEDs3 Safety Population: N=292 <2 seizure medications: 47 (23.4%) Randomized Safety Population: N=201 ≥2 to <4 seizure medications: 85 (42.3%) ≥4 seizure medications: 69 (34.3%) Age (years)1,2 1 Mean: 33 Select Inclusion Criteria Range: 12-62 • Aged ≥12 years ≥12 to <18 years: 10 (5%) • Established diagnosis of epilepsy ≥18 to <65 years: 191 (95%) • On stable regimen of antiepileptic drugs • Adult caregiver able to recognize clusters Sex1,2 and administer treatment Female: 103 (51%) • Documented history of seizure clusters (>3 months before visit 1)a aClusters had to be composed of ≥2 seizures (focal or generalized); last ≥10 minutes; and have an observable, stereotyped, and recognizably different pattern from patients’ noncluster seizure activity, with another seizure occurring within 6 hours of cluster onset. Abbreviation: AEDs, antiepileptic drugs. Sources: 1. Detyniecki K, et al. Epilepsia. 2019;60:1797-1808. 2. NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc. 3. Data on File. UCB Inc.

Seizure Characteristics Cluster Seizure Typesa

NAYZILAM® Placebo Complex partial Secondary Typical cluster duration (min) n=129 n=63 generalized Median 65.00 60.00 Simple partial Range 2.5-4320.0 8.5-2880.0 Primary GTC Seizures per cluster episode n=134 n=67 Median 5.2 6.0 Tonic Range 2-200 2-170 Absence Episodes in year before visit n=134 n=67 NAYZILAM 5 mg (n=134) Median 18 15 Myoclonic Placebo (n=67) Range 3-999 4-600 Atonic Years since clusters onset n=133 n=63 Other Median 5.0 5.0 Range 0.3-48.0 0.5-32.0 0 20 40 60 80 100

Percent of Patients, % aPatients may have reported >1 seizure type. Patients enrolled in ARTEMIS I had several different seizure types, with a median cluster duration of 65 minutes

Abbreviation: GTC, generalized tonic-clonic. Source: Detyniecki K, et al. Epilepsia. 2019;60:1797-1808.

Treatment Response With a Single Dose of NAYZILAM®1,2 100 NAYZILAM 5 mg P=0.110 90 Placebo 80 81% P=0.007 70 P=0.011 70% 60 58% 50 54% 40 37%

30 34% Percent of Patients of Percent 20

10 n=108 n=47 n=78 n=25 n=72 n=23 0 Seizure Termination No Recurrence Treatment <10 min 10 min–6 h Success

In the randomized, double-blind, placebo-controlled trial, the most common adverse reactions (≥5% in any NAYZILAM treatment group) were somnolence, headache, nasal discomfort, throat irritation, and rhinorrhea.1

Sources: 1. NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc. 2. Data on file. UCB Inc.

First Dose (blind)1,2 Second dose (open label)2,3 5 mg NAYZILAM 5 mg NAYZILAM

54% 55%

Treatment Success Treatment Success n=72/134 n=23/42 70% Randomized Treatment First dose (blind)1,2 Second dose (open label)2,3 Groups Placebo 5 mg NAYZILAM Overall Treatment Success2

34% 66% in 122/175a patients treated with NAYZILAM Treatment Success Treatment Success n=23/67 n=27/41

Respiratory depression was observed with the administration of NAYZILAM during clinical trials. Cardiac or respiratory arrest caused by NAYZILAM was not reported during clinical trials.1 aOne hundred seventy-five patients were treated with NAYZILAM: 134 patients in the NAYZILAM arm and 41 patients in the placebo arm.2 Sources: 1. NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc. 2. Data on file. UCB Inc. 3. Detyniecki K, et al. Epilepsia. 2019;60:1797-1808.

Please see additional Important Safety Information within this presentation. Please refer to full Prescribing Information provided by the UCB Representative and visit www.NAYZILAM.com. 30 NAYZILAM-treated Patients Had a Greater Probability of No Seizure Recurrence for 24 Hours Post-dose Probability of Experiencing No Seizures Over the 24‐hour Observation Period Beginning 10 Minutes After Drug Administration1,2

NAYZILAM: 58% 21% difference P=0.0124 Placebo: 37%

NAYZILAM Censored NAYZILAMa Probability of no Seizures noof Probability Placebo Censored Placeboa

Time After Administration of Double-Blind Trial Drug (Hours) Antiepileptic drugs (AEDs), including NAYZILAM, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.1 aPatients who did not have another seizure before the end of the 24‐hour observation period, and who had not been administered the second dose of trial drug, were censored at the end of the observation period. Those administered the second dose of trial drug who did not have a seizure before the administration of the second dose were censored at the time of the second dose.2 Sources: 1. NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc. 2. Detyniecki K, et al. Epilepsia. 2019;60:1797-1808.

Return to Baseline Functionality Within 24 Hours1 Median Time to Return to Full 2,a 100 Baseline Functionality 90 80 70 72.4 60 29.1% difference 50 P<0.0001 40 43.3 30

20 Percent of % of Patients,Percent 10 • Return to baseline comparable to placebo 2 0 (1.4 hours NAYZILAM vs 1.3 hours placebo) NAYZILAM Placebo

Midazolam, including NAYZILAM, is associated with a high incidence of partial or complete impairment of recall for several hours following an administered dose.3 Respiratory depression was observed with the administration of NAYZILAM during clinical trials. Cardiac or respiratory arrest caused by NAYZILAM was not reported during clinical trials.3 aReturn to baseline functionality: time when subject was able to return to what he/she was doing prior to the seizure cluster.1 Abbreviation: AEs, adverse events. Sources: 1. Detyniecki K, et al. Epilepsia. 2019;60:1797-1808. 2. Data on file. UCB Inc. 3. NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc.

NAYZILAMb • The most common adverse Body System/ Placebo + Any NAYZILAM reactions (≥5% in any NAYZILAM Placebo NAYZILAM NAYZILAM Adverse Reactiona NAYZILAM 5 Treatment treatment group) were somnolence, 5 mg 5 mg + 5 mg mg Group headache, nasal discomfort, throat irritation, and rhinorrhea1 N=26 N=91 N=41 N=43 N=175 % % % % % • Most adverse reactions were mild 2 Nervous System or moderate in intensity Somnolence 4 10 10 9 10 • At least one adverse event related Headache 0 7 0 2 4 to acute central respiratory Dysarthria 0 2 2 2 2 depression was reported Application Site in 10 (3.4%) patients2 Nasal Discomfort 8 5 7 16 9 Throat Irritation 0 2 2 7 3 • NAYZILAM was well tolerated. Rhinorrhea 0 3 0 5 3 • No patients discontinued during Product Taste Abnormal 0 4 0 2 0 the comparative phase Eye Disorders of the Phase 3 study of NAYZILAM2 Lacrimation Increased 0 1 2 2 2 aAdverse reactions that occurred within 2 days after NAYZILAM administration are included. bPatients were permitted to take a second, open-label dose of NAYZILAM 5 mg between 10 minutes and 6 hours following the initial blinded dose of NAYZILAM 5 mg or placebo if they experienced seizure recurrence or an incomplete resolution of the episode. The Placebo + NAYZILAM 5 mg and NAYZILAM 5 mg + 5 mg columns represent patients who received a second dose of NAYZILAM 5 mg after receiving a blinded initial dose of placebo or NAYZILAM 5 mg. TEAE, treatment‐emergent adverse event. Sources: 1. NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc. 2. Detyniecki K, et al. Epilepsia. 2019;60:1797-1808.

Maximum Dosage & Dosing Treatment Frequency

1st Dose Administer one spray (5 mg) Do not use more than 2 doses into one nostril of NAYZILAM to treat a single episode

2nd Dose Administer one spray (5 mg) into Treat no more than 1 episode every (if needed) opposite nostril after 10 minutesa 3 days or 5 episodes per month Image is for illustrative purposes only.

• For patients at increased risk of respiratory depression from benzodiazepines, administration under healthcare professional supervision should be considered prior to treatment; this administration may be performed in the absence of a seizure episode.1 • Benzodiazepines, including NAYZILAM, can increase intraocular pressure in patients with glaucoma. NAYZILAM may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. NAYZILAM is contraindicated in patients with narrow-angle glaucoma.1 • Concomitant use of NAYZILAM with moderate or strong CYP3A4 enzyme inhibitors may result in prolonged sedation.1 aIf the patient has not responded to the initial dose. Do not administer if the patient has trouble breathing or if there is excessive sedation uncharacteristic of the patient during a seizure cluster episode.

Source: NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc.

• Can be administered by any non–healthcare professional • No priming or assembly necessary

• Can be administered in an outpatient setting

• May be administered to a patient during or after a seizure within a cluster • Requires no active inhalation; patient may be unconscious

Source: NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc.

Prior to treatment, the healthcare professional should instruct the individual administering on how to identify seizure clusters and use the product appropriately

1. HOLD 2. PLACE 3. PRESS Hold the nasal spray unit with Place the tip of the nozzle into Press the plunger firmly. your thumb on the plunger and one nostril until your fingers are your middle and index fingers on against the bottom of the each side of the nozzle. patient’s nose. Do not press the plunger yet.

Please see the full instructions for use in the Prescribing Information and discuss with the patient and their caregiver.

Source: NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc.

10 MINUTES TO STOP SEIZURE CLUSTERS1 90 MINUTES TO GET PATIENTS BACK TO BASELINE FUNCTION2 • In 81% of patients, NAYZILAM terminated seizure cluster activity • For all seizure clusters treated with NAYZILAM, within 10 minutesa,b the median time to return to full baseline functionalityc after trial drug administration was ~90 minutes2,d No seizure recurrence for up to 6 hours1 • Midazolam, including NAYZILAM, is associated with a high incidence • 58% of patients had no seizure recurrence between of partial or complete impairment of recall for several hours following 10 minutes and up to 6 hours after drug administrationa an administered dose.1 Treatment Success • First dose 54%1 24 HOURS OF NO SEIZURE RECURRENCE • All doses 70%2 IN MAJORITY OF PATIENTS1 • Serious cardiorespiratory adverse reactions have occurred after • Treatment with NAYZILAM significantly prolonged the time administration of midazolam. Warn patients and caregivers about to the next seizure within 24 hours after double-blind study drug the risks of respiratory depression, cardiac and respiratory arrest.1 administration compared with placebo (P=0.012).3 • Respiratory depression was observed with the administration of • In the randomized, double-blind, placebo-controlled trial, NAYZILAM during clinical trials. Cardiac or respiratory arrest the most common adverse reactions (≥5% in any NAYZILAM caused by NAYZILAM was not reported during clinical trials.1 treatment group) were somnolence, headache, nasal discomfort, throat irritation, and rhinorrhea.1 Important Safety Information1 RISKS FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of benzodiazepines, including NAYZILAM, and opioids may result in profound sedation, respiratory depression, coma, and death. • Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. • Limit dosages and durations to the minimum required. • Follow patients for signs and symptoms of respiratory depression and sedation. aBaseline duration of seizure clusters in NAYZILAM arm was a median of 65 minutes (2.5-4320.0 minutes).3 bPrimary endpoint of treatment success included 2 components: the termination of seizures within 10 minutes after the double-blind (first) dose and no recurrence of seizures between 10 minutes and 6 hours (double-blind observation period).1 CExploratory endpoint: time to return to full baseline functionality as determined by the caregiver.3 dRange: 1.1-2.0 hours.2 Sources: 1. NAYZILAM [prescribing information]. Smyrna, GA: UCB Inc. 2. Data on file. UCB Inc. 3. Detyniecki K, et al. Epilepsia. 2019;60:1797-1808.

Please see additional Important Safety Information within this presentation. Please refer to full Prescribing Information provided by the UCB Representative and visit www.NAYZILAM.com. 37 Thank you!