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

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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

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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

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Study design

French JA et al. Epilepsia 2012;

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Study 305

12 mg/day 1210

8

64

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 2 3 4 6 8Randomization

7

Double-blind phase

5

8 mg/day

2

4

6

8

Baseline

6 weeks 4 weeks

Patient flow and disposition

Patient flow and disposition

French JA et al. Epilepsia 2012;

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PlaceboPerampanel

8 mg 12 mg

Assessed for eligibility N 496

Randomized N 389a

Randomized, not treated N 3

ITT analysis set N 136 129 121

Safety analysis set N 136 129 121

Completed (% of safety analysis set) 88% 84% 77%

Discontinued (% of safety analysis set) 12% 16% 23%

Discontinued due to AEs % 3% 9% 19%aIncludes 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

French JA et al. Epilepsia 2012;

Patient demographics and baseline characteristics

Placebo Perampanel

(N=136)8 mg

(N=129)12 mg

(N=121)

Mean age years 34.4 36.7 35.5

Female gender % 47.8% 49.6% 58.7%

Race, %

White 84.6% 82.9% 82.6%

Asian 8.8% 10.9% 13.2%

Black or African American <1% 1.6% <1%

Other 5.9% 4.7% 3.3%Safety analysis set.

Patient demographics

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Study 305

French JA et al. Epilepsia 2012;

Epilepsy-specific medical history

Epilepsy-specific medical history

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Placebo Perampanel

(N=136)8 mg

(N=129)12 mg

(N=121)

Mean time since diagnosis years 22.0 22.5 21.3

Baseline seizure frequencya median 11.8 13.0 13.7

min, max 3.4, 358.4 3.3, 652.2 1.4, 598.4

SZ type, %

SP without motor signs 35.3% 38.0% 29.8%

SP with motor signs 22.1% 30.2% 31.4%

CP 83.8% 88.4% 82.6%

SG 69.9% 69.8% 63.6%aITT population. All other variables are repeated for the safety analysis set.CP: complex partial; SP: simple partial; SG: secondarily generalized.

Study 305

Concomitant AEDsMost patients were taking 2–3 AEDs

% of patients taking 1, 2, and 3 concomitant AEDs, or inducing AEDs, at baseline

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Placebo Perampanel

(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 AEDsa % 52.2% 64.3% 66.1%aAEDs 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

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Concomitant AEDs

% of patients taking the most commonly used AEDsa as 1 of their 1–3 concomitant AEDs

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Placebo Perampanel

(N=136)8 mg

(N=129)12 mg

(N=121)

Levetiracetam 38.2% 38.0% 38.0%

Carbamazepine 31.6% 33.3% 38.8%

Lamotrigine 27.2% 31.0% 22.3%

Valproic acid 23.5% 19.4% 21.5%

Oxcarbazepine 16.9% 19.4% 19.8%

Topiramate 17.6% 19.4% 18.2%

Clobazam 13.2% 10.9% 14.0%

Zonisamide 14.0% 9.3% 9.1%Safety analysis set.

aData shown for AEDs used ≥10% of all patients.French JA et al. Epilepsia 2012; Study 305

*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

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Responder ratea

0

5

10

15

20

25

30

35

40

45

15

33 34

Placebo

Perampanel 8 mg

Perampanel 12 mg

N=

136

N=

129

N=

121

*****

% p

atie

nts

All POS(N=386)

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Mean compliance was ≥98% in each treatment group

-35

-30

-25

-20

-15

-10

-5

0

-10 -8

-31-33

-18

-22

Placebo

Perampanel 8 mg

Perampanel 12 mg

Med

ian

% c

han

ge

N=

136

N=

129

N=

121

N=

126

N=

119

N=

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

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Median % change from baseline in SZ frequency/28 days by seizure type

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Perampanel

8 mg 12 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

Exploratory efficacy endpoints

≥75% seizure reduction and seizure-free rates

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Placebo Perampanel

(N=136)8 mg

(N=129)12 mg

(N=121)

≥75% reduction in seizure frequency1

% patientsa 4.4% 15.5% 16.5%

SZ-free status1

% patients seizure free, excluding drop-outsb 1.7% 2.8% 6.5%

% patients seizure free, pragmatic calculationc 1.5% 2.3% 5.0%aMaintenance period.bMaintenance completers who were seizure free, as a % of the maintenance completer population.cMaintenance completers who were seizure free, as a % of the ITT population, conforming to the “pragmatic ITT” suggested by Gazzola et al.2

1French JA et al. Epilepsia 2012; 2Gazzola et al. Epilepsia 2007;48:1303–1307. Study 305

Exploratory efficacy endpointGlobal impression of change

Global impression of change: proportion of patients with improvement and worsening

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Placebo Perampanel

(N=136)8 mg

(N=129)12 mg

(N=121)

CGIC, %

% patients “very much”, or “much” improved 17.2% 28.8%* 27.3%*

PGIC, %

% patients “very much”, or “much” improved 21.8% 36.7%* 30.6%

% patients “minimally”, “much”, or “very much” worse 11.3% 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

1French JA et al. Epilepsia 2012; (In press); 2Data on file, Eisai Inc.

Safety: overview of AEs

Incidence of AEs1

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Placebo Perampanel

(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

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Safety: most common AEs (1)

Incidence of AEs occurring in ≥10% of patients in any treatment group

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French JA et al. Epilepsia 2012;

Placebo Perampanel

(N=136) 8 mg (N=129)12 mg

(N=121)

AEs occurring in ≥10% of patients in any group, %

Dizziness 7.4% 32.6% 47.9%

Somnolence 2.9% 12.4% 18.2%

Fatigue 8.1% 13.2% 16.5%

Headache 13.2% 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

Study 305

Safety: (2)

Incidence of AEs occurring in >5% of perampanel-treated patients and in at least twice as many perampanel patients than placebo1

1French JA et al. Epilepsia 2012; 2Data on file, Eisai Inc.

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Placebo(N=136)2

Perampanel(N=250)

AEs occurring in >5% of perampanel patients, %

Dizziness 7.4% 40.0%

Somnolence 2.9% 15.2%

Fatigue 8.1% 14.8%

Irritability 3.7% 9.2%

Nausea 3.7% 9.2%

Fall 2.9% 6.0%

Weight increase 2.2% 5.6%Safety analysis set.

Dose–response relationship observed with the exception of weight increase and irritability

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

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Placebo Perampanel

(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%

Somnolence 0 <1% 3.3% 2.0%

Convulsion 2.2% 1.6% <1% 1.2%Safety analysis set.

Placebo Perampanel

(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, %

Dizziness 0 7.8% 17.4% 12.4%

Somnolence 0 3.9% 4.1% 4.0%

Headache 0 0 3.3% 1.6%

Fatigue 0 3.9% 2.5% 3.2%

Ataxia 0 1.6% 2.5% 2.0%

Asthenia 0 2.3% <1% 1.6%Safety analysis set.

Safety: AEs leading to dose adjustments

Rates of drug interruption or dose reduction due to AEs

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French JA et al. Epilepsia 2012 Study 305

Safety: AEs of interestPsychiatric AEs

Incidence of psychiatric AEs

French JA et al. Epilepsia 2012;

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Placebo Perampanel

(N=136)8 mg

(N=129)12 mg

(N=121)

Psychiatric AEs, % 14.0% 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 % 0 1.6% 1.7%

Aggression % <1% 1.6% <1%

Confusional state % 0 0 2.5%

Anger % 0 0 1.7%

Safety analysis set.

Suicidal ideation occurred in 1 patient in the placebo group

Study 305

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

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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;

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Placebo Perampanel

(N=136)8 mg

(N=129)12 mg

(N=121)

SAEs

Patients with SAEs n (%) 7 (5.1%) 10 (7.8%) 12 (9.9%)

Patients discontinuing due to SAEs n 0 4a 3b

Deaths n 0 0 0aPsychotic disorder, ischemic stroke, convulsion, dizziness, nausea, somnolence. bStatus epilepticus/urinary incontinence, somnolence, and belligerence.Safety analysis set.

Study 305

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;

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Study 305

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;

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Study 305

• 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

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