1. © 2014 Direct One Communications, Inc. All rights reserved. 1 Update on Perampanel: A Novel Antiepileptic Drug for Partial-Onset Seizures Angela Wabulya, MB, ChB Johns Hopkins Hospital, Baltimore, Maryland A REPORT FROM THE 67 TH ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY (AES 2013)

2. © 2014 Direct One Communications, Inc. All rights reserved. 2 Mechanism of Action and Usage Perampanel is a selective, orally active, noncompetitive,  -amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) glutamate receptor antagonist Currently approved for adjunctive treatment of partial-onset seizures, with or without secondarily generalized seizures, in more than 30 countries— including the United States, Canada, and the European Union » United States and European Union: approved for use in adults and adolescents  12 years of age » Canada: approved for use in adults  18 years of age

3. © 2014 Direct One Communications, Inc. All rights reserved. 3 Pharmacokinetics Perampanel is quickly and completely absorbed following oral administration, with a median time to maximum plasma concentration (t max ) of 0.75 hour Gidal B et al. AES 2013, Abstract 1.143

4. © 2014 Direct One Communications, Inc. All rights reserved. 4 Pharmacokinetics Administration with food slows perampanel’s absorption. » When ingested with a high-fat meal, t max is delayed by 2–3 hours, and the maximum plasma concentration (C max ) falls by 28%–39%, depending on the dose administered. » However, the overall extent of perampanel absorption is not affected by food. Perampanel is extensively metabolized via cytochrome P3A4. The rate of renal excretion of unchanged perampanel is low (< 0.12%) when compared with its metabolic clearance. Gidal B et al. AES 2013, Abstract 1.143

5. © 2014 Direct One Communications, Inc. All rights reserved. 5 Post Hoc Analyses of Pooled Phase 3 Studies of Perampanel

6. © 2014 Direct One Communications, Inc. All rights reserved. 6 Patient Population and Drug Treatment Patients  12 years of age with refractory partial- onset seizures being treated concomitantly with up to three other antiepileptic drugs (AEDs) After a 6-week baseline period, the patients were randomized in double-blind fashion to receive once- daily doses of 8 or 12 mg of perampanel or placebo (studies 304 and 305) or 2, 4, or 8 mg of perampanel or placebo (study 306). If a patient did not tolerate the assigned randomized dose level, down-titration of the perampanel dosage was permitted. French JA et al. Neurology. 2012;79:589; French JA et al. Epilepsia. 2013;54:117; Krauss GL et al. Neurology. 2012;78:1408.

7. © 2014 Direct One Communications, Inc. All rights reserved. 7 Use of Perampanel with Other AEDs Patients on one AED at baseline were significantly more likely to respond to adjunctive perampanel therapy than patients on three AEDs. The incidence of treatment-emergent adverse events (TEAEs) in patients who received the highest dose of perampanel (12 mg/d) was similar regardless of the number of AEDs being taken concomitantly. The most common TEAEs (  10%) were dizziness, somnolence, and headache. Perampanel therapy generally was safe when used concomitantly with GABA or non-GABA AEDs. Glauser T et al. AES 2013, Abstract 1.230; Muller M et al. AES 2013, Abstract 1.144

8. © 2014 Direct One Communications, Inc. All rights reserved. 8 Use of Perampanel with Other AEDs Muller M et al. AES 2013, Abstract 1.144 Efficacy of perampanel in patients taking concomitant GABA versus non-GABA antiepileptic drugs

9. © 2014 Direct One Communications, Inc. All rights reserved. 9 Lesional vs Nonlesional Partial Epilepsy Response rates for placebo and perampanel were comparable between patients with structural lesions and those who had no lesions. Patients with structural lesions had a lower response rate to 2–8 mg of perampanel than patients without lesions but had a higher response rate than nonlesional patients at 10 and 12 mg of the drug. TEAEs were reported in 66.5% of patients with lesions given placebo and 78.6% of those given perampanel. Among those without lesions, TEAEs occurred in 66.5% of patients receiving placebo and 75.9% of patients receiving perampanel. Marsh S et al. AES 2013, Abstract 2.048

10. © 2014 Direct One Communications, Inc. All rights reserved. 10 Assessment of Liver Toxicity Despite its extensive hepatic metabolism, perampanel has a low hepatotoxic potential. Mean values of hepatobiliary function tests were within normal ranges at baseline and at the end of treatment in both the placebo and perampanel groups. Very small mean changes from baseline to end of therapy were not clinically significant or related to the perampanel dose. None of the patients had values that met the criteria for Hy’s Law (AST or ALT > 3  ULN; bilirubin > 2  ULN, and alkaline phosphatase < 2  ULN). Laurenza A et al. AES 2013, Abstract 1.140

11. © 2014 Direct One Communications, Inc. All rights reserved. 11 Effect on QT Interval Duration In a double-blinded, placebo-controlled study, no clinically significant prolongation of the QT interval was observed in healthy subjects taking 6 or 12 mg of perampanel. Blood samples taken on days 7 and 16 showed no relationship between plasma concentrations of perampanel and QT interval duration. Further, cardiac repolarization in healthy subjects was not affected by either a “mid-therapeutic” dose of perampanel (6 mg/d) or “high-therapeutic” (12 mg/d) dose of the drug. Yang H et al. AES 2013, Abstract 1.141

12. © 2014 Direct One Communications, Inc. All rights reserved. 12 Effect on QT Interval Duration In a post hoc analysis of the three pivotal clinical trials of perampanel, no QT values calculated using Barrett’s formula or Fridericia’s formula exceeded 500 ms in any of the 1,038 patients receiving the drug. In addition, there was no clinically significant difference between the placebo and perampanel groups in the percentage of patients with QTcB or QTcF intervals > 450 ms. Finally, the percentages of patients showing prolongation of the QT interval > 60 ms from baseline were low and comparable between the placebo and perampanel groups. Yang H et al. AES 2013, Abstract 1.141

13. © 2014 Direct One Communications, Inc. All rights reserved. 13 Efficacy and Safety in Elderly Patients Elderly patients (  65 years) enrolled in the three pivotal clinical trials responded to perampanel therapy (8 or 12 mg/d), as measured by the median percent change in seizure frequency at 28 days and responder rates when compared with placebo. Falls and headaches were more common among the elderly than among younger adults, and falls were more frequent in those taking 8 or 12 mg/d. Elderly patients also had a higher percentage of balance and gait disturbances (10% and 15%, respectively) than younger adults (2.9% and 2.8%). Williams B et al. AES 2013, Abstract 1.142

14. © 2014 Direct One Communications, Inc. All rights reserved. 14 Gender Differences In the three pivotal clinical trials, women who were taking perampanel showed a greater reduction in seizure frequency and higher responder rates than men using the drug. Both men and women experienced improved seizure control when using perampanel than when given placebo. Dizziness and headache were more common among women taking perampanel than among men taking the drug. Vasquez B et al. AES 2013, Abstract 1.145

15. © 2014 Direct One Communications, Inc. All rights reserved. 15 Neurologic and Psychiatric Comorbidities Perampanel’s efficacy and safety in patients with partial-onset seizures who had neurologic or psychiatric comorbidities in the three pivotal clinical trials were similar to its efficacy and safety in the overall study population of patients with partial-onset seizures. However, patients with neurologic or psychiatric comorbidities had a higher risk of TEAEs on either perampanel or placebo than did patients who did not have these comorbidities. Squillacote D et al. AES 2013, Abstract 2.049

16. © 2014 Direct One Communications, Inc. All rights reserved. 16 Neurologic and Psychiatric Comorbidities Efficacy of perampanel with and without neurologic and/or psychiatric comorbidities: seizure frequency Squillacote D et al. AES 2013, Abstract 2.049

17. © 2014 Direct One Communications, Inc. All rights reserved. 17 Neurologic and Psychiatric Comorbidities Efficacy of perampanel with and without neurologic and/or psychiatric comorbidities: responder rate Squillacote D et al. AES 2013, Abstract 2.049

18. © 2014 Direct One Communications, Inc. All rights reserved. 18 Onset and Duration of Adverse Events Patients taking perampanel mainly experienced mild or moderate dizziness (28% vs 9% for placebo), somnolence (15% vs 7%), and fatigue (9% vs 5%). During week 1, 4% of patients taking perampanel experienced somnolence and 3% fatigue. The duration of these TEAEs ranged from 1 day to more than 3 months, with a median of 55 days for somnolence and fatigue and 28 days for dizziness. These three TEAEs lead to drug discontinuation in 4% of patients taking perampanel and treatment interruption or dose reduction in another 12%. Ko D et al. AES 2013, Abstract 1.147

19. © 2014 Direct One Communications, Inc. All rights reserved. 19 Psychiatric and Behavioral Reactions The incidence of anxiety, aggression, anger, and sleep disorder was almost twice as high among those using 8 and 12 mg of perampanel as for those using placebo. Overall, 12% of patients on perampanel versus 6% of those on placebo reported hostility/aggression. Psychiatric TEAEs—commonly, insomnia—have been reported in 29% of patients with epilepsy and 18% of healthy control subjects taking perampanel. Homicidal ideation and/or threat were exhibited in 0.1% of 4,368 perampanel-treated patients, including both epilepsy and nonepilepsy populations. Ettinger A et al. AES 2013, Abstract 1.146; Besag FMC, Patsalos PN. Neuropsychiatr Dis Treat. 2012;8:455

20. © 2014 Direct One Communications, Inc. All rights reserved. 20 Hostility and Aggression Hostility and aggression were observed in 3.0% of perampanel patients and 0.7% of the placebo group; 1.6% and 1.2% of perampanel-treated patients reported aggression and anger, respectively. TEAEs leading to discontinuation of perampanel included aggression, anger, and belligerence, mostly among patients taking 12 mg/d. Aggression-related TEAEs were reported in 9.7% of adolescents taking perampanel and none of those using placebo; in adults, they were noted in 1.1% of all patients given perampanel and 0.5% of the placebo group. LoPresti A et al. AES 2013, Abstract 2.050

21. © 2014 Direct One Communications, Inc. All rights reserved. 21 Regional Differences in TEAE Incidence Perampanel was well tolerated across geographic regions for treating drug-resistant partial-onset seizures, at a mean dose of 10.6 mg/d. Dizziness was the most frequent adverse event experienced across regions; it was most common in the China-Pacific region (75%) and least common in Indo-Pacific countries (29%). Depression, insomnia, anxiety, and aggression were the most commonly reported psychiatric TEAEs. Aggression (1%) was the most commonly reported psychiatric significant adverse event. Ben-Menachem et al. AES 2013, Abstract 2.148

22. © 2014 Direct One Communications, Inc. All rights reserved. 22 Reasons for Discontinuation In the extension trial, 505 of 1,216 patients (42%) discontinued perampanel therapy, primarily due to subject choice (14%), adverse events (13%), and/or inadequate seizure control (12%). Dizziness (3.9%) was the most commonly reported adverse event that led to discontinuation, followed by irritability (1.3%). Seizure frequency declined from baseline by 46% among patients exposed to perampanel for more than 9 months and by 60% among those exposed for more than 24 months; 2 of 37 patients (5.3%) were free of seizures at least 1 year. Shih J et al. AES 2013, Abstract 3.211