305 Study

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

2. Study design: Phase III study number: E2007-G000-305 (NCT00699582) 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 French JA et al. Epilepsia 2012; Study 305

3. Study objectives and endpoints CP: complex partial; SG: secondarily generalized; CP+SG: seizures that are either complex partial or secondarily generalized. French JA et al. Epilepsia2012 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 Study 305

4. Study design Follow-up phase or OLE Pre-randomization Double-blind phase 6 weeks 4 weeks 6-week titration period 13-week maintenance period 12 12 mg/day Baseline 10 8 8 mg/day 8 6 6 4 4 2 2 Placebo arm Visit 1 9 2 3 4 5 6 7 8 Follow-up OLE Enrolment Randomization French JA et al. Epilepsia 2012; Study 305

5. Patient flow and disposition Patient flow and disposition French JA et al. Epilepsia 2012; Study 305

6. Patient demographics Patient demographics and baseline characteristics French JA et al. Epilepsia 2012; Study 305

7. Epilepsy-specific medical history Epilepsy-specific medical history French JA et al. Epilepsia 2012; Study 305

8. Concomitant AEDsMost patients were taking 2–3 AEDs % of patients taking 1, 2, and 3 concomitant AEDs, or inducing AEDs, at baseline Mean number of concomitant AEDs at baseline was 2.3 French JA et al. Epilepsia 2012; Study 305

9. Concomitant AEDs % of patients taking the most commonly used AEDsa as 1 of their 1–3 concomitant AEDs aData shown for AEDs used ≥10% of all patients.French JA et al. Epilepsia 2012; Study 305

10. Responder ratea Primary efficacy endpoint:Responder rate *** % patients ** Mean compliance was ≥98% in each treatment group N=136 N=129 N=121 All POS(N=386) *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; Study 305

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

12. Exploratory efficacy endpoints ≥75% seizure reduction and seizure-free rates 1French JA et al. Epilepsia 2012; 2Gazzola et al. Epilepsia 2007;48:1303–1307. Study 305

13. Exploratory efficacy endpointGlobal impression of change Global impression of change: proportion of patients with improvement and worsening CGIC: clinician global impression of change; PGIC: patient global impression of change.French JA et al. Epilepsia 2012; Study 305

14. Safety: overview of AEs Incidence of AEs1 1French JA et al. Epilepsia 2012; (In press); 2Data on file, Eisai Inc. Study 305

15. Safety: most common AEs (1) Incidence of AEs occurring in ≥10% of patients in any treatment group Majority of AEs were mild or moderate Despite longer duration of maintenance period, incidence of AEs was no higher during maintenance than titration French JA et al. Epilepsia 2012; 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 placebo1 Dose–response relationship observed with the exception of weight increase and irritability 1French JA et al. Epilepsia 2012; 2Data on file, Eisai Inc.

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

18. Safety: AEs leading to dose adjustments Rates of drug interruption or dose reduction due to AEs French JA et al. Epilepsia2012 Study 305

19. Safety: AEs of interestPsychiatric AEs Incidence of psychiatric AEs • Suicidal ideation occurred in 1 patient in the placebo group French JA et al. Epilepsia 2012; Study 305

20. Safety: AEs of interestFalls 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 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; 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; 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; Study 305

24. Conclusions • 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 perampanel8mg 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). Study 305