Study 307- Long term open label extension data Krauss GL, Perucca E, Ben-Menachem E, Kwan P, Shih JJ, Squillacote D, Yang H, Gee M, Zhu J, Laurenza A Perampanel, a selective, non-competitive AMPA receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim results from Phase III, extension study 307 Epilepsia 2013 Jan;54(1): Fycompa-EU0042 Date of preparation: August

Study 307 Phase III Study 307: part of comprehensive Phase III clinical development plan for perampanel 3 Phase III studies of adjunctive perampanel in patients with refractory POS rolled into extension study Krauss GL et al. Neurology 2012;78(18):1408–1415; 2 French JA et al. Neurology 2012;79:589–596; 3 French JA et al. Epilepsia. Epub 20 Aug 2012; 4 Krauss et al. Epilepsia Jan;54(1): Perampanel data on file PER008, August Efficacy, safety 706 patients Low-dose study (2, 4, and 8 mg) Efficacy, safety 388 patients (304) 386 patients (305) High-dose studies (8 and 12 mg) Extension study, N=1218 Patients rolled in from: 5 304: N= : N= : N=595

IVRS=Interactive voice-response system; Krauss et al. Epilepsia Jan;54(1): Enrollment (visit 8 of the double-blind study) Study design Follow-up phase (4-weeks) Double-blind study final dose Blinded conversion period (16-week duration) Visit: 1 Maintenance period (256-week duration) End of trial Follow- up Placebo arm 2 mg 4 mg 8 mg 12 mg 6 mg 10 mg mg or MTD N (enrolled)= % of double-blind completers entered the OLE N (enrolled)= % of double-blind completers entered the OLE 3 Study 307 Titration every 2 weeks

Design An extension study for patients completing the double-blind phase of 3 core Phase III trials (studies 304, 305, and 306) – Blinded conversion period: patients were titrated in 2 mg increments every 2 weeks during a 16-week period to their individual maximum tolerated dose (MTD, maximum 12 mg) – Open-label maintenance period: up to 256 weeks Participants Patients aged ≥12 years who had completed 1 of the double-blind Phase III studies Uncontrolled partial-onset seizures despite treatment with 1–3 approved AEDs 249 study sites in 39 countries Analysis period First patient in (FPI), October 2008 Cut-off date for the interim analyses was – December 2010 – 120 day safety update - November 2011 Treatments Open-label perampanel 12 mg or maximum tolerated dose (MTD) – Once daily, at bedtime, with food – Patients who could not tolerate at least 2 mg were discontinued Study design 4 Krauss et al. Epilepsia Jan;54(1): Study 307

Study objectives and endpoints Study objectives Primary: To evaluate long-term safety and tolerability of perampanel as an adjunctive treatment for refractory POS Secondary: To evaluate the maintenance effect of perampanel for treatment of refractory POS Safety assessments Adverse events (AEs), vital signs, clinical laboratory values, body weight, and ECGs Seizure-related endpoints Median % change from pre-perampanel baseline in SZ frequency per 28 days Responder rate: % of patients with ≥50% reduction from pre-perampanel baseline in SZ frequency Krauss et al. Epilepsia Jan;54(1): Study 307

Patients Completed double-blind Phase III studyN1264 Entered study 307N1218 ITT analysis setN1207 Patients excluded from safety analysis a N32 Safety analysis setN1186 Ongoing (% of safety analysis set)70.8% Discontinued (% of safety analysis set)29.2% Primary reason for discontinuation: Adverse events%10.5% Subject choice %9.0% Inadequate therapeutic effect %7.4% Other 2 %2.3% a Patients who enrolled in study 307 but had no extension study post-dose safety data at cut-off date Patient characteristics and disposition (Dec 2010) Patient characteristics and disposition 1 1 Krauss et al. Epilepsia Jan;54(1):126-34; 2 Data on File, Eisai Inc. 6 Study 307

Patient demographics and pre-perampanel baseline a characteristics Patients (N=1186) Mean ageyears34.3 Male/female%50.4% / 49.6% Mean BMIkg/m Race, % White %74.3% Asian%21.1% Black or African American%1.9% Other%2.7% a For patients taking placebo in the core Phase III studies, pre-perampanel baseline uses all data from the double-blind study; for patients taking perampanel in the core studies, pre-perampanel baseline was computed from baseline period of these studies. Safety analysis set. Patient demographics 7 Study 307 Krauss et al. Epilepsia Jan;54(1):126-34

Study 307 Krauss et al. Epilepsia Jan;54(1): Epilepsy history Most patients were taking 2 or more AEDs Epilepsy history at baseline a 8 Patients (N=1186) Seizure frequency b median (range)11.2 (1.2–4503.9) % patients taking 1 concomitant AED n, % % 2 AEDs n, % % 3 AEDs n, % % Most common concomitant AED c Carbamazepinen, % % Valproic acidn, % % Lamotriginen, % % Levetiracetamn, % % Topiramaten, % % Oxcarbazepinen, % % a Baseline data from double-blind study baseline, unless otherwise indicated. b Based on pre-perampanel data, including core Phase III studies for patients taking placebo in the double-blind studies. c Data shown for AEDS used in ≥10% of all patients. Safety analysis set. Study % were taking 2 or more AEDs Mean number of AEDs: % were taking 2 or more AEDs Mean number of AEDs: 2.2

Study 307 Extent of exposure to perampanel Nearly 50% of patients received perampanel for >1 year Krauss et al. Epilepsia Jan;54(1): Study 307 Cumulative extent of patient exposure to perampanel (%) Duration 49% exposed to perampanel for >1 year Median exposure: 51.4 weeks (1.1–128.1) Duration 49% exposed to perampanel for >1 year Median exposure: 51.4 weeks (1.1–128.1) Dose 91.4% received 10 or 12 mg/day Mean dose: 10.1 mg Dose 91.4% received 10 or 12 mg/day Mean dose: 10.1 mg Exposure duration (weeks) <4 mg (N=1) 4 mg (N=15) >4–8 mg (N=86) >8–12 mg (N=1084) Total (N=1186) >4073.3%95.3%100%99.2% >8060.0%83.7%97.7%96.1% > %79.1%95.5%93.8% > %75.6%93.7%91.8% > %59.3%83.4%81.0% > %41.9%67.2%64.8% > %29.1%50.9%48.9% > %16.3%34.5%33.0% > %22.4%21.1% Duration of perampanel treatment includes the double-blind phase for patients who took perampanel in the core Phase III studies, and includes just the extension phase for patients who took placebo in the core studies. Safety analysis set.

Study 307 Incidence of AEs % of patients experiencing AEs Krauss et al. Epilepsia Jan;54(1): <4 mg (N=1) 4 mg (N=15) >4–8 mg (N=86) >8–12 mg (N=1084) Total (N=1186) Any AEs%100%86.7%96.5%86.7%87.4% Severe AEs%013.3%18.6%14.1%14.4% Mild or moderate AEs73.0% Treatment related%086.7%95.3%76.8%78.2% Serious AEs (SAE)%013.3%12.8%13.3%13.2% AEs leading to: Discontinuation%100%40.0%26.7%11.7%13.2% Dose reduction %066.7%80.2%32.2%36.1% Dose interruption%002.3%3.4%3.3% AEs are reported for the entire duration of perampanel exposure (including the double-blind phase for patients who took perampanel in the core Phase III studies). AEs reported here are treatment-emergent AEs (AEs that occurred from the first day of perampanel administration to 30 days after the last dose of perampanel, or that were present before the first day of perampanel administration but worsened in severity during the study). Safety analysis set. Study 307

Most common AEs occurring in ≥10% subjects Krauss et al. Epilepsia Jan;54(1): <4 mg (N=1) 4 mg (N=15) >4–8 g/day (N=86) >8–12 mg (N=1084) Total (N=1186) Dizziness060.0%59.3%42.5%43.9% Somnolence020.0%26.7%19.7%20.2% Headache013.3%27.9%15.9%16.7% Fatigue013.3%15.1%11.8%12.1% AEs are reported for the entire duration of perampanel exposure (including the double-blind phase for patients who took perampanel in the core Phase III studies). Safety analysis set. Study 307 Incidence of AEs occurring in ≥10% of patients As duration of exposure to each dose of perampanel varied in this study, it was not possible to determine if the incidence of AEs was dose-related

Study 307 Other common AEs Krauss et al. Epilepsia Jan;54(1): <4 mg (N=1) 4 mg (N=15) >4–8 mg (N=86) >8–12 mg (N=1084) Total (N=1186) Irritability06.7%9.3%9.9%9.8% Nasopharyngitis002.3%7.8%7.3% Fall06.7%5.8%6.9%6.8% Nausea013.3%8.1%6.6%6.8% Weight increased003.5%7.2%6.8% Ataxia0011.6%5.8%6.2% Gait disturbance008.1%5.7%5.8% Convulsion003.5%5.7%5.5% Vertigo06.7%8.1%5.3%5.5% Balance disorder005.8%5.4% Vomiting013.3%05.6%5.3% Upper resp. tract infection06.7%5.8%5.2% AEs are reported for the entire duration of perampanel exposure (including the double-blind phase for patients who took perampanel in the core Phase III studies). Safety analysis set. Study 307 Incidence of AEs occurring in ≥5% and <10% of patients

Study 307 Serious adverse events AEs are reported for the entire duration of perampanel exposure (including the double-blind phase for patients who took perampanel in the core Phase III studies). Safety analysis set. Krauss et al. Epilepsia Jan;54(1): Study 307 Serious adverse events (SAEs) occurred in 13.2% of patients The only SAEs that occurred in >1% patients were those related to seizures –Reported by n=24 patients (2%) Status epilepticus was reported as an SAE in 9 (<1%) patients Non-seizure-related SAEs that occurred in >5 patients were –Aggression (n=10, <1%), –Psychotic disorder (n=6, <1%) –Suicidal ideation (n=6, <1%) Hospitalization was required in 4 of these patients; perampanel was discontinued in 4 3 deaths occurred –1 due to a road traffic accident, 1 due to sudden unexpected death in epilepsy, and 1 due to cerebral hemorrhage –None of the deaths were considered to be related to study treatment

Study 307 Incidence of worsening seizures a Defined as a >50% increase in seizure frequency compared with pre-perampanel baseline. Krauss et al. Epilepsia Jan;54(1): Previously randomized group PBO2 mg4 mg8 mg12 mg End of conversion period (N=1207)% 8.7%4.8%5.8%7.6%11.0% After 1 year (N=239) %4.7%02.5%8.3%10.7% Analysis period represents the entire duration of perampanel exposure (including the double-blind phase for patients who took perampanel in the core Phase III studies). Safety analysis set. Study 307 Patients (%) with worsening seizures a Incidence of worsening seizures did not increase between end of conversion phase and 1 year of maintenance phase

Study 307 Laboratory values and vital signs There was a low incidence (0–4.5%) of markedly abnormal laboratory values – 3-times the ULN –1.7% of patients had CPK levels >5-times the ULN The majority of markedly abnormal laboratory values at double-blind baseline were in patients taking concomitant carbamazepine, oxcarbazepine, or valproic acid: –34 of all 34 patients with abnormally low sodium –41 of the 50 patients with low neutrophil values –14 of the 24 patients with markedly low white blood cell count No clinically important changes in ECG parameters –No patients had a QTcF or QTcB value >500 ms – 60 ms change from baseline in QTcF or QTcB Few patients (2%) had clinically notable changes in systolic or diastolic blood pressure (≥20 mmHg or ≥15 mmHg change, respectively) AST=aspartate aminotransferase; ALT=alanine aminotransferase; ULN=upper limit of normal; CPK=creatinine phosphokinase. Analysis period represents the entire duration of perampanel exposure (including the double-blind phase for patients who took perampanel in the core Phase III studies). Safety analysis set. Krauss et al. Epilepsia Jan;54(1):

Study 307 Changes in weight after 50 weeks of perampanel exposure Patient weight Krauss et al. Epilepsia Jan;54(1): Study 307 ≤4 mg (N=4) 6 or 8 mg (N=27) 10 or 12 mg (N=629) Absolute change from baselinekg Mean change from baseline at 50 weeks Patients with clinically notable change% >7% increase from baseline29.5% >7% decrease from baseline7.6% Analysis period represents the first 50 weeks of perampanel exposure (including the double-blind phase for patients who took perampanel in the core Phase III studies). Safety analysis set.

Study 307 Efficacy endpoints: change in SZ frequency Sustained effect over duration of perampanel exposure Duration of perampanel treatment includes the double-blind phase for patients who took perampanel in the core Phase III studies, and includes just the extension phase for patients who took placebo in the core studies. ITT population. Krauss et al. Epilepsia Jan;54(1): Median % change from pre-perampanel baseline in SZ frequency/28 days, by 13-week interval Study % reduction in SZ frequency at 2 years 47% reduction in SZ frequency at 1 year

Study 307 Efficacy endpoints: change in SZ frequency From double-blind study through extension ITT population. Krauss et al. Epilepsia Jan;54(1): Median % change from pre-perampanel baseline in seizure frequency/28 days Core Phase III Open-label extension Maintenance period (weeks) Study 307 N=369N=838N=369N=817N=237N=589N=164N=422 N=119 N=291 N=64 N=175 N=29N=71 N=7 N=21

Study 307 Efficacy endpoints: responder rate Sustained increase over duration of perampanel exposure a % patients with ≥50% reduction in seizure frequency. Duration of perampanel treatment includes the double-blind phase for patients who took perampanel in the core Phase III studies, and includes just the extension phase for patients who took placebo in the core studies. Krauss et al. Epilepsia Jan;54(1): Responder rate a by 13-week interval relative to pre-perampanel baseline 63% of patients are responders at 2 years 48% of patients are responders at 1 year

Study 307 Efficacy endpoints: responder rate From double-blind study through extension a % patients achieving ≥50% reduction in seizure frequency/28 days compared with pre-perampanel baseline. ITT population. Krauss et al. Epilepsia Jan;54(1): Responder rate a Core Phase III Open-label extension Maintenance period (weeks) N=369N=838N=369N=817N=237N=589N=164N=422N=119N=291N=64N=175N=29N=71N=7N=21

Study 307 Efficacy endpoint: seizure freedom Duration of perampanel treatment includes the double-blind phase for patients who took perampanel in the core Phase III studies, and includes just the extension phase for patients who took placebo in the core studies. Krauss et al. Epilepsia Jan;54(1): Seizure-free rate by duration of perampanel exposure

Study 307 Conclusions Long-term adjunctive perampanel (mean dose 10 mg/day) has a favorable tolerability profile in patients with refractory partial-onset seizures –Retention rate was >70% after average treatment duration of nearly 1 year –Long-term safety and tolerability were consistent with Phase II and III clinical trial data –Most frequent adverse events were dizziness, somnolence, headache, and fatigue –No new safety events were reported Long-term perampanel treatment maintains the efficacy improvements seen in the double-blind studies, with data up to 2 years –Patients converting from placebo quickly matched efficacy improvements seen in double-blind studies –Improvements in seizure frequency and responder rate were seen at end of conversion period compared with double-blind maintenance period These are likely to reflect the up-titration of perampanel dose Krauss et al. Epilepsia Jan;54(1):