Study 307- Long term open label extension data - PowerPoint Presentation

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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 307Epilepsia 2013 Jan;54(1):126-34Fycompa-EU0042 Date of preparation: August 2013

1

Phase III

Study 307: part of comprehensive Phase III clinical development plan for perampanel3 Phase III studies of adjunctive perampanel in patients with refractory POS rolled into extension study 3072

1

K

rauss 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

3

074

3061

Efficacy, safety706 patientsLow-dose study (2, 4, and 8 mg)

Efficacy, safety388 patients (304)386 patients (305)High-dose studies(8 and 12 mg)

Extension study, N=1218Patients rolled in from:5304: 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)

456712End of trialFollow-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

DesignAn 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 weeksParticipantsPatients aged ≥12 years who had completed 1 of the double-blind Phase III studiesUncontrolled partial-onset seizures despite treatment with 1–3 approved AEDs249 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

TreatmentsOpen-label perampanel 12 mg or maximum tolerated dose (MTD)Once daily, at bedtime, with foodPatients who could not tolerate at least 2 mg were discontinuedStudy design4

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

Study objectives and endpointsStudy objectivesPrimary: 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 POSSafety assessmentsAdverse events (AEs), vital signs, clinical laboratory values, body weight, and ECGsSeizure-related endpointsMedian % 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

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Epilepsia

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2013 Jan;54(1):126-34. 5

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 analysis

a

N

32

Safety analysis set N

1186Ongoing (% 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 (

D

ec 2010)

Patient characteristics and disposition

1

1

Krauss

et al

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Epilepsia

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2013 Jan;54(1):

126-34

;

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Data on File, Eisai Inc.

6

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/m

2

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 demographics7Study 307Krauss et al. Epilepsia. 2013 Jan;54(1):126-34

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

Epilepsy historyMost patients were taking 2 or more AEDsEpilepsy history at baselinea8

Patients

(N=1186)

Seizure frequency

b

median (range)

11.2 (1.2–4503.9)

% patients taking 1 concomitant AED n,

%

15913.4%

2 AEDs n, %596

50.3%3 AEDs n, %43136.3%

Most common concomitant AEDc

Carbamazepine n, %40033.7%

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%

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 307

86% were taking 2 or more AEDs

Mean number of AEDs: 2.2

Extent of exposure to perampanelNearly 50% of patients received perampanel for >1 yearKrauss et al.

Epilepsia. 2013 Jan;54(1):126-349Study 307Cumulative 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 mgExposure duration(weeks)

<4 mg(N=1)4 mg

(N=15)>4–8 mg(N=86)>8–12 mg

(N=1084)

Total(N=1186) >4

073.3%

95.3%100%99.2%

>8060.0%83.7%

97.7%96.1%>120

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.

Incidence of AEs% of patients experiencing AEsKrauss

et al. Epilepsia. 2013 Jan;54(1):126-3410

<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 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

Most common AEs occurring in ≥10% subjectsKrauss et al.

Epilepsia. 2013 Jan;54(1):126-34.11

<4 mg

(N=1)

4 mg

(N=15)

>4–8 g/day

(N=86)

>8–12 mg

(N=1084)Total(N=1186)

Dizziness

060.0%

59.3%42.5%43.9%

Somnolence020.0%

26.7%19.7%20.2%

Headache013.3%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

Other common AEsKrauss et al. Epilepsia

. 2013 Jan;54(1):126-3412

<4 mg

(N=1)

4 mg

(N=15)

>4–8 mg

(N=86)

>8–12 mg

(N=1084)Total (N=1186)

Irritability

06.7%9.3%

9.9%9.8%

Nasopharyngitis00

2.3%7.8%7.3%Fall

06.7%5.8%6.9%

6.8%

Nausea

0

13.3%

8.1%

6.6%

6.8%

Weight increased

0

0

3.5%

7.2%

6.8%

Ataxia

0

0

11.6%

5.8%

6.2%

Gait disturbance

0

0

8.1%

5.7%

5.8%

Convulsion

0

0

3.5%

5.7%

5.5%

Vertigo

0

6.7%

8.1%

5.3%

5.5%

Balance disorder

0

0

5.8%

5.4%

5.4%

Vomiting

0

13.3%

0

5.6%

5.3%

Upper resp. tract infection

0

6.7%

5.8%

5.2%

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

Serious adverse eventsAEs 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):126-34.13Study 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 occurred1 due to a road traffic accident, 1 due to sudden unexpected death in epilepsy, and 1 due to cerebral hemorrhageNone of the deaths were considered to be related to study treatment

Incidence of worsening seizuresaDefined as a >50% increase in seizure frequency compared with pre-perampanel baseline.

Krauss et al. Epilepsia. 2013 Jan;54(1):126-3414

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 307Patients (%) with worsening seizuresaIncidence of worsening seizures did not increase between end of conversion phase and 1 year of maintenance phase

Laboratory values and vital signsThere 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 ULNThe 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 sodium41 of the 50 patients with low neutrophil values14 of the 24 patients with markedly low white blood cell countNo clinically important changes in ECG parametersNo 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

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Epilepsia. 2013 Jan;54(1):126-3415

Changes in weight after 50 weeks of perampanel exposure

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

16

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

1.72.3Patients 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.

Efficacy endpoints: change in SZ frequencySustained 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. 2013 Jan;54(1):126-34.17

Median % change from pre-perampanel baseline in SZ

frequency/28 days, by

13-week interval

Study 307

56% reduction in SZ frequency at 2 years

47% reduction in SZ frequency at 1 year

Efficacy endpoints: change in SZ frequency

From double-blind study through extensionITT population. Krauss et al. Epilepsia. 2013 Jan;54(1):126-34.18

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

Core Phase III

Open-label extension

Maintenance period (weeks)

Study 307

N=369

N=838N=369

N=817N=237N=589N=164N=422N=119N=291

N=64N=175

N=29N=71N=7N=21

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. 2013 Jan;54(1):126-34.19

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

Efficacy endpoints: responder rate

From double-blind study through extensiona% 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 rate

a

Core Phase III

Open-label extension

Maintenance period (weeks)

N=369N=838N=369N=817N=237

N=589N=164N=422N=119N=291N=64N=175N=29

N=71

N=7N=21

Efficacy endpoint: seizure freedomDuration 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):126-3421

Seizure-free rate by duration of perampanel exposure

ConclusionsLong-term adjunctive perampanel (mean dose 10 mg/day) has a favorable tolerability profile in patients with refractory partial-onset seizuresRetention 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 dataMost frequent adverse events were dizziness, somnolence, headache, and fatigueNo new safety events were reportedLong-term perampanel treatment maintains the efficacy improvements seen in the double-blind studies, with data up to 2 yearsPatients converting from placebo quickly matched efficacy improvements seen in double-blind studiesImprovements in seizure frequency and responder rate were seen at end of conversion period compared with double-blind maintenance periodThese are likely to reflect the up-titration of perampanel dose

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