1. 305 Study Randomised, Double Blind, Placebo Controlled Phase III Safety and Efficacy Study (8 and 12 mg OD) Conducted in Europe, Asia, North America, Australia, and South Africa 1

2. Design Randomized, double-blind, placebo-controlled, multicenter study of the efficacy and safety of perampanel when added to 1–3 approved AEDs in patients with uncontrolled partial- onset seizures (POS) 6-week baseline phase followed by a 19-week double-blind treatment phase (6-week titration and 13-week maintenance) 4-week follow up, or entry into open-label extension (OLE) Participants Patients ≥12 years of age with refractory (uncontrolled) POS, with or without secondary generalization Uncontrolled seizures (SZs) despite treatment with ≥2 different AEDs within the past 2 years During 6-week baseline phase had ≥5 POS and receive stable doses of 1–3 AEDs 78 centers in Africa, America, Asia, Australia, Europe, and Russia Treatments 8 or 12 mg of perampanel or matched placebo once daily Study design: Phase III study number: E2007-G000-305 (NCT00699582) French JA et al. Epilepsia 2012; Study 305 2

3. Study objectives and endpoints Study objectives Primary: evaluate efficacy of 2 doses of perampanel (8 and 12 mg) Secondary: evaluate the safety and tolerability of perampanel Primary efficacy endpoints Responder rate (% of patients with ≥50% reduction from baseline in SZ frequency) Median % change from baseline in SZ frequency per 28 days Secondary efficacy endpoints Median % change from baseline in frequency of CP+SG SZs Safety assessments Prior and concomitant medication use, AEs, discontinuations, vital signs, clinical labs, ECGs, physical and neurological examinations, photosensitivity and withdrawal questionnaires CP: complex partial; SG: secondarily generalized; CP+SG: seizures that are either complex partial or secondarily generalized. French JA et al. Epilepsia 2012 3 Study 305

4. Study design French JA et al. Epilepsia 2012; 4 Study 305 12 mg/day 12 10 8 6 4 2 Follow-up 9 Follow-up phase or OLE OLE 13-week maintenance period Pre- randomization 6-week titration period Enrolment Placebo arm Visit 1 23468 Randomization 7 Double-blind phase 5 8 mg/day 2 4 6 8 Baseline 6 weeks4 weeks

5. Patient flow and disposition French JA et al. Epilepsia 2012; 5 Placebo Perampanel 8 mg12 mg Assessed for eligibilityN496 Randomized N 389 a Randomized, not treated N3 ITT analysis set N136129121 Safety analysis set N136129121 Completed (% of safety analysis set)88%84%77% Discontinued (% of safety analysis set)12%16%23% Discontinued due to AEs %3%9%19% a Includes 8 patients who were screen failures and inappropriately randomized to a treatment group. ITT: intent-to-treat analysis set (all randomized patients who received study drug and had any seizure frequency data collected from the double-blind phase). Study 305

6. French JA et al. Epilepsia 2012; Patient demographics and baseline characteristics PlaceboPerampanel (N=136) 8 mg (N=129) 12 mg (N=121) Mean age years34.436.735.5 Female gender %47.8%49.6%58.7% Race, % White84.6%82.9%82.6% Asian8.8%10.9%13.2% Black or African American<1%1.6%<1% Other5.9%4.7%3.3% Safety analysis set. Patient demographics 6 Study 305

7. French JA et al. Epilepsia 2012; Epilepsy-specific medical history 7 PlaceboPerampanel (N=136) 8 mg (N=129) 12 mg (N=121) Mean time since diagnosis years22.022.521.3 Baseline seizure frequency a median 11.813.013.7 min, max3.4, 358.43.3, 652.21.4, 598.4 SZ type, % SP without motor signs35.3%38.0%29.8% SP with motor signs22.1%30.2%31.4% CP83.8%88.4%82.6% SG69.9%69.8%63.6% a ITT population. All other variables are repeated for the safety analysis set. CP: complex partial; SP: simple partial; SG: secondarily generalized. Study 305

8. Concomitant AEDs Most patients were taking 2–3 AEDs % of patients taking 1, 2, and 3 concomitant AEDs, or inducing AEDs, at baseline 8 PlaceboPerampanel (N=136) 8 mg (N=129) 12 mg (N=121) 1 AED %12.5%12.4%7.4% 2 AEDs %47.1%52.7%52.1% 3 AEDs %40.4%34.9%40.5% Perampanel-inducing AEDs a %52.2%64.3%66.1% a AEDs shown to induce clearance of perampanel were carbamazepine, oxcarbazepine, and phenytoin. Safety analysis set. French JA et al. Epilepsia 2012; Mean number of concomitant AEDs at baseline was 2.3 Study 305

9. Concomitant AEDs % of patients taking the most commonly used AEDs a as 1 of their 1–3 concomitant AEDs 9 PlaceboPerampanel (N=136) 8 mg (N=129) 12 mg (N=121) Levetiracetam38.2%38.0% Carbamazepine31.6%33.3%38.8% Lamotrigine27.2%31.0%22.3% Valproic acid23.5%19.4%21.5% Oxcarbazepine16.9%19.4%19.8% Topiramate17.6%19.4%18.2% Clobazam13.2%10.9%14.0% Zonisamide14.0%9.3%9.1% Safety analysis set. a Data shown for AEDs used ≥10% of all patients. French JA et al. Epilepsia 2012; Study 305

10. *P≤0.05; **P≤0.01 ***P≤0.001, vs placebo. a % of patients achieving ≥50% reduction from baseline in SZ frequency, ITT population. Maintenance LOCF. French JA et al. Epilepsia 2012; Primary efficacy endpoint: Responder rate 10 Responder rate a N=136N=129N=121 *** ** % patients All POS (N=386) Study 305 Mean compliance was ≥98% in each treatment group

11. Median % change N=136N=129N=121 N=126N=119N=113 All POS (Primary endpoint) CP+SG (Secondary endpoint) *** * ** *P≤0.05; **P≤0.01 ***P≤0.001, vs placebo. ITT population. Double-blind phase. French JA et al. Epilepsia 2012; Primary and secondary efficacy endpoints: Median % change in SZ frequency 11 Median % change from baseline in SZ frequency/28 days by seizure type Study 305 Perampanel 8 mg12 mg Median difference % -19.1%-13.7% 95% CI-29.2, -8.4-25.2, -2.3 Median differences in % change in SZ frequency (all POS) vs placebo

12. Exploratory efficacy endpoints ≥75% seizure reduction and seizure-free rates 12 PlaceboPerampanel (N=136) 8 mg (N=129) 12 mg (N=121) ≥75% reduction in seizure frequency 1 % patients a 4.4%15.5%16.5% SZ-free status 1 % patients seizure free, excluding drop-outs b 1.7%2.8%6.5% % patients seizure free, pragmatic calculation c 1.5%2.3%5.0% a Maintenance period. b Maintenance completers who were seizure free, as a % of the maintenance completer population. c Maintenance completers who were seizure free, as a % of the ITT population, conforming to the “pragmatic ITT” suggested by Gazzola et al. 2 1 French JA et al. Epilepsia 2012; 2 Gazzola et al. Epilepsia 2007;48:1303–1307. Study 305

13. Exploratory efficacy endpoint Global impression of change Global impression of change: proportion of patients with improvement and worsening 13 PlaceboPerampanel (N=136) 8 mg (N=129) 12 mg (N=121) CGIC, % % patients “very much”, or “much” improved17.2%28.8%*27.3%* PGIC, % % patients “very much”, or “much” improved21.8%36.7%*30.6% % patients “minimally”, “much”, or “very much” worse11.3%12.5%20.4% *P≤0.05 vs placebo. ITT population. CGIC: clinician global impression of change; PGIC: patient global impression of change. French JA et al. Epilepsia 2012; Study 305

14. 1 French JA et al. Epilepsia 2012; (In press); 2 Data on file, Eisai Inc. Safety: overview of AEs Incidence of AEs 1 14 PlaceboPerampanel (N=136) 8 mg (N=129) 12 mg (N=121) Patients with any AE %68.4%86.8%86.0% Mild AEs % 31.6%39.5%28.9% Moderate AEs % 30.1%38.0%46.3% Severe AEs % 6.6%9.3%10.7% AEs considered treatment-related % 47.8%69.0%77.7% Patients with SAEs n (%) 7 (5.1%)10 (7.8%)12 (9.9%) AEs: treatment-emergent adverse events (an adverse event that began on or after the date of first study drug and occurred up to 30 days after the date of the last study drug dose, or began before the date of first study drug and increased in severity during the treatment period). 2 Study 305

15. Safety: most common AEs (1) Incidence of AEs occurring in ≥10% of patients in any treatment group 15 French JA et al. Epilepsia 2012; PlaceboPerampanel (N=136) 8 mg (N=129) 12 mg (N=121) AEs occurring in ≥10% of patients in any group, % Dizziness7.4%32.6%47.9% Somnolence2.9%12.4%18.2% Fatigue8.1%13.2%16.5% Headache13.2%8.5%13.2% Safety analysis set. Majority of AEs were mild or moderate Despite longer duration of maintenance period, incidence of AEs was no higher during maintenance than titration Majority of AEs were mild or moderate Despite longer duration of maintenance period, incidence of AEs was no higher during maintenance than titration Study 305

16. Safety: (2) Incidence of AEs occurring in >5% of perampanel-treated patients and in at least twice as many perampanel patients than placebo 1 1 French JA et al. Epilepsia 2012; 2 Data on file, Eisai Inc. 16 Placebo (N=136) 2 Perampanel (N=250) AEs occurring in >5% of perampanel patients, % Dizziness7.4%40.0% Somnolence2.9%15.2% Fatigue8.1%14.8% Irritability3.7%9.2% Nausea3.7%9.2% Fall2.9%6.0% Weight increase2.2%5.6% Safety analysis set. Dose–response relationship observed with the exception of weight increase and irritability

17. Safety: AEs leading to discontinuation Rates of discontinuation due to AEs Rash led to discontinuation in 4 (1.6%) perampanel patients vs none in the placebo group French JA et al. Epilepsia 2012 17 PlaceboPerampanel (N=136) 8 mg (N=129) 12 mg (N=121) Total (N=250) Discontinuation due to AEs, %4.4%9.3%19.0%14.0% Discontinuation >2% of patients, in any treatment group, % Dizziness<1%2.3%5.0%3.6% Somnolence0<1%3.3%2.0% Convulsion2.2%1.6%<1%1.2% Safety analysis set.

18. PlaceboPerampanel (N=136) 8 mg (N=129) 12 mg (N=121) Total (N=250) Dose interruption/reduction due to AEs, %3.7%20.9%28.1%24.4% Dose interruption/reduction >2% of patients in any treatment group, % Dizziness07.8%17.4%12.4% Somnolence03.9%4.1%4.0% Headache003.3%1.6% Fatigue03.9%2.5%3.2% Ataxia01.6%2.5%2.0% Asthenia02.3%<1%1.6% Safety analysis set. Safety: AEs leading to dose adjustments Rates of drug interruption or dose reduction due to AEs 18 French JA et al. Epilepsia 2012 Study 305

19. Safety: AEs of interest Psychiatric AEs Incidence of psychiatric AEs French JA et al. Epilepsia 2012; 19 PlaceboPerampanel (N=136) 8 mg (N=129) 12 mg (N=121) Psychiatric AEs, %14.0% 17.4% Psychiatric AEs occurring in >1% of patients, and more frequent in any perampanel group than placebo, % Sleep disorder% <1%2.3%1.7% Anxiety% 01.6%1.7% Aggression % <1%1.6%<1% Confusional state% 002.5% Anger % 001.7% Safety analysis set. Suicidal ideation occurred in 1 patient in the placebo group Study 305

20. Safety: AEs of interest Falls Incidence of fall – 31 falls were reported in 19 patients Placebo: 4 falls in 4 placebo patients (2.9%) Perampanel: 27 falls in 15 perampanel patients (6.0%) –7 out of 15 patients in the perampanel group had multiple episodes of fall (up to 5 in total) –5 perampanel patients experienced falls at daily doses lower than 8 mg Timing of falls – exact timing not recorded in case report forms 3 of 4 falls in placebo patients and 9 of 27 falls in perampanel patients occurred on the same day as secondarily generalized seizures AEs in patients with falls – Many patients also complained of other CNS side effects Unsteady gait, ataxia, dizziness, and slurred speech Relationship to exposure – increased with plasma concentration PK/PD analysis showed probability of fall (grouped with gait disturbance and balance disorder), increased with increasing average plasma concentration of perampanel Discontinuation – No discontinuations were related to falls or injury Concomitant AEDs in patients with falls Similar distribution to overall trial population French JA et al. Epilepsia 2012 20 Study 305

21. Safety: serious adverse events Serious adverse events The only SAEs occurring in >1% of patients were epilepsy related –Occurred in 6 patients: 2 (1.5%) placebo, 3 (2.3%) 8 mg, and 1 (<1%) 12 mg perampanel Six patients had SAEs related to injury: 0, 3, and 3, respectively, in the placebo and perampanel 8 mg and 12 mg groups –Result of fall (n=3) or seizure with fall (n=3) –Injury was the only SAE seen more than twice (7 SAEs of injury occurring in 6 patients) French JA et al. Epilepsia 2012; 21 PlaceboPerampanel (N=136) 8 mg (N=129) 12 mg (N=121) SAEs Patients with SAEsn (%)7 (5.1%)10 (7.8%)12 (9.9%) Patients discontinuing due to SAEsn04a4a 3b3b Deathsn000 a Psychotic disorder, ischemic stroke, convulsion, dizziness, nausea, somnolence. b Status epilepticus/urinary incontinence, somnolence, and belligerence. Safety analysis set. Study 305

22. Safety: serious adverse events Non-epilepsy-related SAEs –There were 29 non-epilepsy-related SAEs in 25 patients (5 patients in the placebo group, and 8 in the 8 mg and 12 in the 12 mg perampanel groups) Psychiatric SAEs were uncommon –Occurred in 5 patients (<2% of total) and were evenly distributed between placebo and perampanel groups Dermatological SAEs –No reports of dermatological SAEs –No reports of Stevens–Johnson syndrome Perampanel-related SAEs –No specific event was consistently considered to be perampanel related with the exception of 2 SAEs of convulsion in the 8 mg group French JA et al. Epilepsia 2012; 22 Study 305

23. Safety: additional considerations Laboratory values, ECGs, vital signs, physical/neurological exams –No clinically important changes Increases in weight –>7% increase from baseline: 4.4% (placebo), 11.6% (perampanel), no apparent dose effect –Mean weight changes from baseline: −0.1 kg (placebo), +1.1 kg (8 mg), +1.3 kg (12 mg perampanel) Seizure worsening (>50% increase in seizure frequency from baseline) –10% (placebo), 8% (8 mg), 9% (12 mg perampanel) Abuse and diversion –No reports of abuse or diversion of perampanel Overdose: all 10 were accidental; 8 were blister pack mistakes –2 (placebo), 5 (8 mg), and 3 (12 mg perampanel) Photosensitivity questionnaire: 8 positive responses –2 (2.2%) placebo; 4 (4.9%) 8 mg, 2 (2.4%) 12 mg perampanel –No dose changes or discontinuations required French JA et al. Epilepsia 2012; 23 Study 305

24. In patients with refractory POS, adjunctive therapy with perampanel 8 mg/day and 12 mg/day significantly reduced seizure frequency compared with placebo Secondary and exploratory efficacy endpoints support the primary findings –Seizure freedom was attained in up to 6.5% of patients –More than 3-times as many perampanel patients achieved ≥75% seizure reductions than placebo patients –Both the CGIC and PGIC showed significant improvement with perampanel (PGIC for perampanel 8mg only) The most common AEs were predominantly CNS related (dizziness, somnolence, fatigue and headache) –Discontinuation rates due to AEs were low and comparable with other AED trials –Falls occurred at a greater rate in perampanel-treated patients, although exposure adjusted rates were low There were few positive responses on the photosensitivity questionnaire The results of this study add to the encouraging clinical evidence for the value of AMPA receptor antagonists in the epilepsy armamentarium French JA et al. Epilepsia 2012; (In press). Conclusions 24 Study 305