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 APerampanel, 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):126-34

Fycompa-EU0042 Date of preparation: August 2013

1

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 307

2

1Krauss GL et al. Neurology 2012;78(18):1408–1415; 2French JA et al. Neurology 2012;79:589–596; 3French JA et al. Epilepsia. Epub 20 Aug 2012; 4Krauss et al. Epilepsia. 2013 Jan;54(1):126-34

5Perampanel data on file PER008, August 2012

3042

3053

3074

3061

• 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=311305: N=312306: N=595

IVRS=Interactive voice-response system; Krauss et al. Epilepsia. 2013 Jan;54(1):126-34.

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)

4 5 6 7 12 End of trial

Follow-up

Placebo arm

2 mg

4 mg

8 mg

12 mg

6 mg

10 mg

2

4

6

8

10

12 mg or MTD

N (enrolled)=1218

96.4% 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

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Krauss et al. Epilepsia. 2013 Jan;54(1):126-34Study 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. 2013 Jan;54(1):126-34.

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Study 307

Study 307

Patients

Completed double-blind Phase III study N 1264

Entered study 307 N 1218

ITT analysis set N 1207

Patients excluded from safety analysisa N 32

Safety analysis set N 1186

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%

Other2 % 2.3%

aPatients 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 disposition1

1Krauss et al. Epilepsia. 2013 Jan;54(1):126-34; 2Data on File, Eisai Inc.

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Study 307

Study 307

Patient demographics and pre-perampanel baselinea characteristics

Patients(N=1186)

Mean age years 34.3

Male/female % 50.4% / 49.6%

Mean BMI kg/m2 25.0

Race, %

White % 74.3%

Asian % 21.1%

Black or African American % 1.9%

Other % 2.7%aFor 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 307Krauss et al. Epilepsia. 2013 Jan;54(1):126-34

Study 307Krauss et al. Epilepsia. 2013 Jan;54(1):126-34.

Epilepsy historyMost patients were taking 2 or more AEDs

Epilepsy history at baselinea

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Patients (N=1186)

Seizure frequencybmedian (range) 11.2 (1.2–4503.9)

% patients taking 1 concomitant AED

n, %159 13.4%

2 AEDs n, % 596 50.3%

3 AEDs n, % 431 36.3%

Most common concomitant AEDc

Carbamazepine n, % 400 33.7%

Valproic acid n, % 399 33.6%

Lamotrigine n, % 374 31.5%

Levetiracetam n, % 344 29.0%

Topiramate n, % 239 20.2%

Oxcarbazepine n, % 213 18.0%aBaseline data from double-blind study baseline, unless otherwise indicated. bBased on pre-perampanel data, including core Phase III studies for patients taking placebo in the double-blind studies. cData shown for AEDS used in ≥10% of all patients. Safety analysis set.

Study 307

86% were taking 2 or more AEDsMean number of AEDs: 2.2

Study 307

Extent of exposure to perampanelNearly 50% of patients received perampanel for >1 year

Krauss et al. Epilepsia. 2013 Jan;54(1):126-34

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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)

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)

>4 0 73.3% 95.3% 100% 99.2%

>8 0 60.0% 83.7% 97.7% 96.1%

>12 0 60.0% 79.1% 95.5% 93.8%

>16 0 53.3% 75.6% 93.7% 91.8%

>28 0 40.0% 59.3% 83.4% 81.0%

>40 0 26.7% 41.9% 67.2% 64.8%

>52 0 20.0% 29.1% 50.9% 48.9%

>64 0 20.0% 16.3% 34.5% 33.0%

>76 0 0 8.1% 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. 2013 Jan;54(1):126-34

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<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 % 0 13.3% 18.6% 14.1% 14.4%

Mild or moderate AEs 73.0%

Treatment related % 0 86.7% 95.3% 76.8% 78.2%

Serious AEs (SAE) % 0 13.3% 12.8% 13.3% 13.2%

AEs leading to:

Discontinuation % 100% 40.0% 26.7% 11.7% 13.2%

Dose reduction % 0 66.7% 80.2% 32.2% 36.1%

Dose interruption % 0 0 2.3% 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

Study 307

Most common AEs occurring in ≥10% subjects

Krauss et al. Epilepsia. 2013 Jan;54(1):126-34.

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<4 mg(N=1)

4 mg(N=15)

>4–8 g/day(N=86)

>8–12 mg(N=1084)

Total(N=1186)

Dizziness 0 60.0% 59.3% 42.5% 43.9%

Somnolence 0 20.0% 26.7% 19.7% 20.2%

Headache 0 13.3% 27.9% 15.9% 16.7%

Fatigue 0 13.3% 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

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. 2013 Jan;54(1):126-34.

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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

aDefined as a >50% increase in seizure frequency compared with pre-perampanel baseline. Krauss et al. Epilepsia. 2013 Jan;54(1):126-34

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Previously randomized group

PBO 2 mg 4 mg 8 mg 12 mg

End of conversion period (N=1207) % 8.7% 4.8% 5.8% 7.6% 11.0%

After 1 year (N=239) % 4.7% 0 2.5% 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 seizuresa

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– <1% of patients had AST or ALT levels >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

– <1% patients had a >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. 2013 Jan;54(1):126-34

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Study 307

Changes in weight after 50 weeks of perampanel exposure

Patient weight

Krauss et al. Epilepsia. 2013 Jan;54(1):126-34

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Study 307

≤4 mg(N=4)

6 or 8 mg(N=27)

10 or 12 mg(N=629)

Absolute change from baseline kg

Mean change from baseline at 50 weeks 0.9 1.7 2.3

Patients with clinically notable change%

>7% increase from baseline 29.5%

>7% decrease from baseline 7.6%

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

Blinded conversion

period 1-13 14-26 27-39 40-52 53-65 66-78

-42

-49 -50

-56

-49-52

-62

-42

-47-49

-54

-49

-63 -62

Maintenanc...

-70

-60

-50

-40

-30

-20

-10

0

-19

-32

Prior placebo Prior perampanel

Me

dia

n c

ha

ng

e (

%)

Efficacy endpoints: change in SZ frequencyFrom double-blind study through extension

ITT population. Krauss et al. Epilepsia. 2013 Jan;54(1):126-34.

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Median % change from pre-perampanel baseline in seizure frequency/28 days

Core Phase III Open-label extension

Maintenance period (weeks)

Study 307

N=

36

9

N=

83

8

N=

36

9

N=

81

7

N=

23

7

N=

58

9

N=

16

4

N=

42

2

N=

119

N=

29

1

N=

64

N=

17

5

N=

29

N=

71

N=

7

N=

21

Study 307

Maintenance...0

10

20

30

40

50

60

70

80

21

34

Prior placebo Prior perampanel

Re

sp

on

de

r ra

te (

%)

Blinded conversion

period

1-13 14-26 27-39 40-52 53-65 66-78

4449 49

56

4752

71

4347 49

5347

5962

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. 2013 Jan;54(1):126-34

20

Responder ratea

Core Phase III Open-label extension

Maintenance period (weeks)

N=

36

9

N=

83

8

N=

36

9

N=

81

7

N=

23

7

N=

58

9

N=

16

4

N=

42

2

N=

119

N=

29

1

N=

64

N=

17

5

N=

29

N=

71

N=

7

N=

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. 2013 Jan;54(1):126-34

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6 months 9 months 12 months0

5

10

15

20

8.97.6 7.1

Duration of perampanel treatment

% s

eizu

re-f

ree

pat

ien

ts

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. 2013 Jan;54(1):126-34

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