New Antiepileptic Medications

Drug Profiles, Efficacy, Safety, and Tolerability

Evolving Epilepsy TherapyEvolving Epilepsy Therapy

• Treatments– First-generation AEDs

1930-1980s

– Second-generation AEDs 1984-2006

– Third-generation AEDs 2006-today

– Orphan AEDs

• Needs– Tolerability– Safety– Added efficacy

Recent AEDsRecent AEDsDrug Company

FDA Approval Indication

Clobazam(Onfi®) Lundbeck 2011 Adjunctive therapy for LGS in patients ≥ 2 y

Eslicarbazepine(Aptiom®)

Sunovion (Sepracor + Dainippon)

20132015 Monotherapy or adjunctive therapy for POS

Lacosamide(Vimpat®) UCB Pharma 2008

2014Monotherapy or adjunctive therapy for POS

in patients ≥ 17 y

Perampanel(Fycompa™) Eisai 2012

2015Adjunctive therapy for POS and PGTC seizures

in patients ≥ 12 y

Retigabine/Ezogabine (Potiga®)

GSK/Valeant 2011 Adjunctive therapy for POS in patients ≥ 18 y

Rufinamide (Banzel®) Eisai 2008

2013 Adjunctive therapy for LGS in patients ≥ 1 y

Vigabatrin (Sabril®) Lundbeck 2009

2013Monotherapy for infantile spasms

Adjunctive therapy for CPS in patients ≥ 10 y

ClobazamClobazam

• Summary: 1,5-benzodiazepine (N ring position)– GABAA receptor binding (Cl flux)

– Affinity for ω2 instead of ω1 subunit

– Thus less sedation and tolerance than 1,4-benzodiazepines (eg, clonazepam)

– T1/2 = 18 hours

– Metabolized by several CYP with an active metabolite norclobazam

– Indicated for adjunctive treatment of multiple seizure types in Canada, Japan; anxiety indication in United Kingdom

Clobazam (cont) Clobazam (cont)

• Effective for drop seizures in LGSa

– Ages 2 to 60; N = 238

– Doses of 0.25 and 1 mg/kg/d

– Weekly titration, initial 5 to 10 mg/d

– Maximum dosage 40 mg/d

• FDA approved for LGS in 2011 (orphan drug approval 2008)

• Approved in Europe, Canada

a. Ng YT, et al. Neurology. 2011;77:1473-1481.[1]

Clobazam (cont)

Placebo (n = 57)

Low Dosage (n = 53)

Medium Dosage (n

= 58)

High Dosage (n = 49)

0

10

20

30

40

50

60

70

80

12.1

41.249.4

68.3

9.3

34.8

45.3

65.3

Drop seizuresTotal (drop and nondrop) seizures

(95% CI, 24.9-57.6)P = .0120

(95% CI, 28.1%-62.5%P = .0044

(95% CI, 51.5-85.1)P < .0001

Mea

n D

ecre

ase

in S

eizu

re R

ate,

%

(95% CI, −3.6 to 27.8)

(95% CI, −7.6 to 26.3)

(95% CI, 17.2-52.5)P = .0414

(95% CI, 47.2-83.5)P < .0001

(95% CI, 33.4-65.4)P = .0015

Ng YT, et al. Neurology. 2011;77:1473-1481.[1]

EslicarbazepineEslicarbazepine

• Demonstrated efficacy up to 1200 mg with daily dosing in 3 pivotal trials (all conducted outside United States)

• Effective in monotherapy trials with up to 1600 mg/day

• Chemically related; MOA same as with carbamazepine and oxcarbazepine

− Forms S-licarbazepine (OXC-MHD = S + R licarbazepine)

• Significant drug interactions with oral contraceptives and some other AEDs, including phenytoin

• Most common adverse events were dizziness, headache, diplopia, and somnolence

Stephen LJ, et al. CNS Drugs. 2011;25:89-107.[2]; Elger C, et al. Epilepsia. 2007;48:497-504.[3]; Jacobson MP, et al. BMC Neurology. 2015:15:46.[4]; Sperling MR, et al. Epilepsia. 2015;56:546-55.[5]

• Shares dibenzazepine nucleus with CBZ and OXC, but with 5-carboxamide substitute

• Primarily converted toS-licarbazepine

• 4% converted to R-licarbazepine via oxcarbazepine

Stephen LJ, et al. CNS Drugs. 2011;25:89-107.[2]; Elger C, et al. Epilepsia. 2007;48:497-504.[3]

5%

Oxcarbazepine Eliscarbazepine acetate

R(-)-licarbazepine S(+)-licarbazepine

EslicarbazepineChemical Structure

Placebo ESL 400 mg ESL 800 mg ESL 1200 mg

Study 301 Study 302

50

45

40

35

30

25

20

15

10

5

0

*

%

50

45

40

35

30

25

20

15

10

5

0

††

%

Median Relative Reduction in Seizure Frequency

Responder Rate

n = 402 n = 393 n = 252 n = 402 n = 393 n = 252

*P < .001; †P < .05.

Eslicarbazepine Pivotal Trial Results Percent Reduction in Seizure Frequency and 50% Responder Rate

*

* *

* *

†*

Study 303 Study 301 Study 302 Study 303

McCormack PL, et al. CNS Drugs. 2009;23:71-79.[6]

EslicarbazepinePhase 3 Treatment-Emergent Adverse Events

EslicarbazepinePhase 3 Treatment-Emergent Adverse Events

Treatment-Emergent Adverse Events With ≥ 10% Incidence Rates

BIA-2093-301 BIA-2093-302Placebo(n = 102)

ESL 400 mg/d(n = 100)

ESL 800 mg/d(n = 98)

Placebo(n = 100)

ESL 400 mg/d(n = 96)

ESL 800 mg/d(n = 101)

Any TEAE 31.4 44.0 50.0 68.0 78.1 83.2

Dizziness 2.0 4.0 14.3 10.0 22.9 29.7

Headache 5.9 5.0 9.2 9.0 8.3 14.9

Diplopia 0 2.0 7.1 4.0 8.3 14.9

Somnolence 2.0 6.0 9.2 17.0 15.6 16.8

NR = not reported.Incidence rates are for approved doses.

• Other AEs (NR in 301): nausea (range 4.0-11.9), abnormal coordination (5.0-12.9), vomiting (3.0-12.9)

Elger C, et al. Epilepsia. 2009;50:454-63.[7]; Ben-Menachem E, et al. Epilepsy Res. 2010;89:278-85.[8]

Eslicarbazepine Monotherapy Conversion TrialKaplan–Meier-Estimated 112-Day Exit Rate

Eslicarbazepine Monotherapy Conversion TrialKaplan–Meier-Estimated 112-Day Exit Rate

Jacobson MP, et al. BMC Neurology. 2015:15:46. ESL 1200 mg ESL 1600 mg0

10

20

30

40

50

60

70

Cum

ulati

ve E

xit R

ate

at 1

12 D

ays

(KM

Esti

mat

e), %

; 95%

CI

65.3% lower confidence limit of historical controls

12.8 (7.5-21.5)

15.6 (8.1-28.7)

Jacobson MP, et al. BMC Neurology. 2015:15:46.[4]

LacosamideLacosamide

• Lacosamide therapy:− Indicated as

monotherapy or adjunctive therapy in the management of POS in adult patients with epilepsy

• Enhancement of slow inactivation of sodium channels

• Functionalized amino acid with similarity to D-serine

(R)-2-acetzamido-N-benzyl-3-methoxypropionamide

R(+) configuration is active Molecular weight: 250.3Water solubility: 27 mg/mL

LacosamidePharmacokinetic ProfileLacosamidePharmacokinetic Profile• Predictable and dose-

proportional PK profile

• Tmax: 0.25 to 4 hours after oral administration

• t½ ~ 13 hours (twice-a-day dosing)

• Absolute bioavailability ~100%

• Volume of distribution ~0.6 L/kg

• Renally excreted (95%)

• Low potential for drug-drug interactions

• Bioequivalence of oral and IV (30- and 60-minute infusions)

• Low protein binding (<15%)

• No food interaction has been observed

• Low inter- and intra-subject variability (~ 20%)

• No influence of gender or race observed

Vimpat® PI 2015.[9]

n = 359 n = 267 n = 466 n = 202

ITT – indirect comparison of results between 3 studies

Med

ian

Redu

ction

, %

21

37 38† †

10

26

39 40† †

36*

†

21

35

0

10

20

30

40

50

60 SP667a

SP755c

SP754b

Placebo LCM 200 mg/d LCM 400 mg/d LCM 600 mg/d

*P < .05; †P < .01. P values based on log-transformed data from pairwise treatment using ANCOVA models.ITT = Intent to treat (randomized subjects receiving at least 1 dose of trial medication with ≥ 1 post-baseline efficacy assessment). The approved daily dose for lacosamide is up to 400 mg/day; 600 mg/d is above the FDA recommended dose.

Lacosamide: Median Percent Reduction in Seizure Frequency Per 28 Days: Baseline to Maintenance, Per Randomized Dose

a. Ben-Menachem E, et al. Epilepsia. 2007;48:1308-17.[10]; b. Chung S, et al. Epilepsia. 2010;51:958-67.[11]; c. Halász P, et al. Epilepsia. 2009;50:443-53.[12]

Adverse Event (%) MedDRA Preferred Term

Placebon = 364

Lacosamide

200 mg/dn = 270

400 mg/dn = 471

600 mg/dn = 203

Total N = 944

Dizziness 8 16 30 53 31

Headache 9 11 14 12 13

Nausea 4 7 11 17 11

Diplopia 2 6 10 16 11

Vomiting 3 6 9 16 9

Fatigue 6 7 7 15 9

Vision blurred 3 2 9 16 8

Coordination abnormal 2 4 7 15 8

Safety population, N = 1308; the approved dosage for lacosamide is up to 400 mg/d.Pooled safety data from 3 randomized, double-blind, placebo-controlled Phase 2/3 clinical trials, each trial included a 4- to 6-week titration phase followed by a 12-week maintenance phase. Safety population included adults (16-70 years of age) with POS, with or without secondary generalization, and taking 1-3 concomitant antiepileptic drugs.

Lacosamide Safety and Tolerability: Pooled Pivotal Trial Data Adverse Events Occurring (≥ 10%) During the Treatment Phase

Chung S, et al. CNS Drugs. 2010;24:1041-1054.[13] Gil-Nagel A, et al. IEC 2009. Poster 508.[14]

Current Therapy + Placebo

Current Therapy + LCM 200 mg/d

Current Therapy + LCM 400 mg/d

Current Therapy + LCM 600 mg/d

01020304050607080

23.1

34.844.3 48.6

Pooled Phase 2/3 Trial Data

≥ 50

% R

espo

nder

Rat

e, %

‡

n = 337 n = 244 n = 393 n = 142

Lacosamide Optimizing Combination Therapy ≥ 50% Responder Rate in Patients Taking ≥ 1 Concomitant Sodium-channel Blocking AEDs (ITTm Population*)

†

*The modified ITT (ITTm) population (N = 1116) included all randomized patients receiving ≥ 1 dose of trial medication with ≥ post-baseline efficacy assessment, excluding those who discontinued during the titration phase. †P < .05; ‡ P < .01 vs placeboThe approved daily dosage for lacosamide is ≤ 400 mg/day.

Sake J, et al. CNS Drugs. 2010;24:1055-1068[15]; Isojarvi J, et al. ECE 2010. Poster 230.[16]

‡

MedDRA Preferred Term

Infusion duration 30 min, N = 40n (%)

Headache 3 (8)

Dizziness 3 (8)

Diplopia 2 (5)

Nausea 2 (5)

Somnolence 4 (10)

Fatigue 0 (0)

Abdominal pain, upper 0 (0)

WBC urine positive 2 (5)

Infusion reactions 3 (8)

Krauss G, et al. Epilepsia. 2010;51:951-957.[17]

Lacosamide Infusion AEs

Lacosamide Monotherapy Conversion TrialKaplan–Meier-Estimated 112-Day Exit RateLacosamide Monotherapy Conversion TrialKaplan–Meier-Estimated 112-Day Exit Rate

Wechsler RT, et al. Epilepsia. 2014;55:1088-1098.[18]

Kapl

an-M

eier

Pre

dict

ed E

xit P

erce

ntag

e

Primary Assessment Secondary Assessment0

102030405060708090

100

30 32.3

Lacosamide 400 mg/d

Patients meeting ≥ 1 exit criterion during the

Lacosamide Maintenance Phase, FAS

Patients meeting ≥ 1 exit criterion, withdrawals due to a TEAE, and

withdrawals due to lack of efficacy during the Lacosamide

Maintenance Phase, FAS

65.3% lower confidence limit of historical controls

Perampanel Selective Antagonist for the AMPA Subtype of Ionotropic Glutamate Receptors

5'-(2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl-6'(1'H)-one

Chemical Structure

Percentage of patients experiencing ≥ 50% reduction in seizure frequency (ITT) –

maintenance (LOCF) period vs baseline

Median percentage reductions in seizure frequency per 28 days (ITT)– double-blind

phase vs baseline

10.69

13.63(P = ns*)

23.33(P = .003*)

30.8(P < .001*)

0

5

10

15

20

25

30

35

40

1

Med

ian

Perc

enta

ge C

hang

e (R

educ

tion)

in

Sez

iure

Fre

quen

cy

Placebo Perampanel 2 mg Perampanel 4 mg Perampanel 8 mg

Krauss GL, et al. Neurology. 2012;78:1408-15.[19]

Perampanel Study 306 Median Percentage Reduction in Seizure Frequency and 50% Responder Rate

* = vs placebo

n = 184 n = 180 n = 172 n = 169 n = 184 n = 180 n = 172 n = 1690

5

10

15

20

25

30

35

40

17.9

20.6

28.5

34.9

Resp

onde

r Rat

e Pe

rcen

tage

of P

atien

ts

(P = NS*)

(P = .013*)

(P < .001*)

Med

ian

Perc

enta

ge C

hang

e (R

educ

tion)

in S

eizu

re F

requ

ency

Perampanel Treatment-Emergent Adverse EventsPerampanel Treatment-Emergent Adverse Events

Incidence of TEAEs (Safety Population)Patients, n (%)

Placebon = 185

2 mg/dn = 180

4 mg/dn = 172

8 mg/dn = 169

Any AE 101 (54.6) 111 (61.7) 111 (64.5) 121 (71.6)Any TEAE 59 (31.9) 67 (37.2) 77 (44.8) 96 (56.8)Any TEAE leading to study/treatment discontinuation 7 (3.8) 12 (6.7) 5 (2.9) 12 (7.1)Any TEAE leading to dose reduction/interruption 6 (3.2) 3 (1.7) 12 (7.0) 29 (17.2)Any serious TEAE 9 (4.9) 6 (3.3) 6 (3.5) 6 (3.6)TEAEs in ≥ 5% (any treatment group)

Dizziness 18 (9.7) 18 (10.0) 28 (16.3) 45 (26.6) Somnolence 12 (6.5) 22 (12.2) 16 (9.3) 27 (16.0) Headache 16 (8.6) 16 (8.9) 19 (11.0) 18 (10.7) Fatigue 5 (2.7) 8 (4.4) 13 (7.6) 9 (5.3)

Upper respiratory tract infection 5 (2.7) 11 (6.1) 6 (3.5) 3 (1.8) Nasopharyngitis 3 (1.6) 7 (3.9) 9 (5.2) 3 (1.8) Gait disturbance 2 (1.1) 1 (< 1) 2 (1.2) 9 (5.3)

Krauss GL, et al. Neurology. 2012;78:1408-15.[19]

Perampanel for the Treatment of Refractory PGTC SeizuresPerampanel for the Treatment of Refractory PGTC Seizures

French JA, et al. Neurology. 2015. [Epub ahead of print].[20]

Median % Change From Baseline in PGTC Seizure

Frequency

50% PGTC Seizure Responder Rate

Tonic Clonic Seizure-free Rate

-100

-80

-60

-40

-20

0

20

40

60

80

-76.5

64.2

30.9

-38.4

39.5

12.3

Perampanel (N = 81) Placebo (N = 81)

P < .0001

P = .0019

Retigabine/EzogabineRetigabine/Ezogabine

• Novel MOA with activation of neuronal M-current mediated by KCNQ (Kv7) voltage-gated potassium channelsa

• Half-life of 8 to 11 hoursa

• 3x-per-day dosing (extended-release formulation in development)

• Limited potential for drug-drug interactions with other AEDsb

− Phenytoin and carbamazepine may increase the clearance of retigabine

• Smooth muscle relaxant in rodents (bladder distention)b

a. Luszczki JJ. Pharmacol Rep. 2009;61:197-216.[21]; b. Bialer M, et al. Epilepsy Res. 2009;83:1-43.[22]

*P < .047 for overall difference across retigabine 300, 600, and 1200 mg/d arms†P < .001 for overall difference across all treatment arms

Intent-to-Treat Population

Placebo 600 mg/d 900 mg/d 1200 mg/d

-50

-40

-30

-20

-10

0

-13.1

-23.4†-29.3†

-35.2

Chan

ge in

Tot

al M

onth

lyPa

rtial

-sei

zure

Fre

quen

cy, %

Retigabine*

Retigabine Dose-Ranging Trial for POS Primary Efficacy ResultsRetigabine Dose-Ranging Trial for POS Primary Efficacy Results

Porter RJ, et al. Neurology. 2007;68:1197-1204.[23]

Retigabine Dose-ranging Trial for Partial-Onset SeizuresAdverse Events

Retigabine Dose-ranging Trial for Partial-Onset SeizuresAdverse Events

Table shows range of incidence in all 3 dosage groups (600, 900, 1200 mg/d). Only AEs with incidence ≥ 17% at the 1200 mg/day dose are shown.*P < .05 for placebo vs the combined retigabine groups for incidence of treatment-emergent AEs.

Placebo, % (n = 96)

Retigabine*, % (n = 301)

CNS Related

Somnolence 6.3* 17.0-22.6

Confusion 5.2* 5.0-22.6

Dizziness 4.2* 8.0-17.9

Other

Headache 10.4* 11.0-17.0

Porter RJ, et al. Neurology. 2007;68:1197-1204.[23]

Retigabine Safety ConcernsRetigabine Safety Concerns

• Retigabine carries a black box warning for retinal abnormalities and potential vision loss− Retinal abnormalities reported > 4 yr of exposure

− Seen in one-third of patients

• Retigabine can cause blue skin discoloration− Reported in 10% of patients after ≥ 2 yr of exposure

− Appears as blue pigmentation on/around lips, finger/toe nail beds, scattered over body

− Discoloration of the palate, sclera, and conjunctiva also reported

• Urinary retention− Reported in 2% of patients exposed to retigabine

Potiga® PI 2015.[24]

RufinamideRufinamide

• Currently has orphan approval for the add-on treatment of seizures associated with LGS

• Prolongs the inactive state of voltage-dependent sodium channels and limits sustained repetitive firing of sodium-dependent action potentials

• Unsuccessful trials: monotherapy, pediatric POS, primary generalized epilepsy; indication for adjunctive POS not pursued

• Limited potential for drug-drug interactions− Valproic acid interaction in children

(increases rufinamide levels up to 70% in small children)a

Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25]

Rufinamide for Adjunctive Treatment in Lennox-Gastaut Syndrome Efficacy

Rufinamide Placebo-50

-40

-30

-20

-10

0

10

20

-42.5

1.4

-32.7

11.7

Red

uct

ion

, %

Rufinamide Placebo05

1015202530354045 42.5

16.7

31.1

10.9≥

50%

Res

po

nd

ers,

%

Tonic-atonic seizures Total seizures

Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25]

Rufinamide TolerabilityRufinamide Tolerability

Adverse events occurring in patients treated with rufinamide vs placebo

Adverse Event

Rufinamide

Placebo

Short-term Therapy, %(N = 1875)

Long-term Therapy, %

(N = 1978)Headache 22.9 29.5 18.9

Dizziness 15.5 22.5 9.4

Fatigue 13.6 17.7 9.0

Somnolence 11.8 n/a 9.1

Nausea 11.4 n/1 7.6

Serious AEs 6.3 13.2 3.9

Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25]

Rufinamide for Adjunctive Treatment of Partial Seizures50% Responder Rate

Rufinamide for Adjunctive Treatment of Partial Seizures50% Responder Rate

*P = .027; †P = .012; ‡P = .016.

14‡

94.7

16* 12†

0

10

20

30

40

Placebo 200 mg/d 400 mg/d 800 mg/d 1600 mg/d

Resp

onde

r Rat

e, %

Rufinamide

Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25]

RufinamideAdditional StudiesRufinamideAdditional Studies

• Monotherapy– 2 studies assessed monotherapy; neither was positive

on primary end point• Partial-onset pediatric– Greater reduction in seizure frequency for placebo than

rufinamide• Primary generalized tonic-clonic– Reduced frequency of generalized tonic-clonic seizures

by 36.4%, compared to 25.6% for placebo, but results were not significant

• As a result of these studies, an indication for POS was not pursued

Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25]

Rufinamide DosingRufinamide Dosing

• Approved: rapid 1-week titration schedule

– In pediatrics, an initial dosage of 10 mg/kg/d with an increase of 10 mg/kg/d every 2 days up to a target dosage of 45 mg/kg/d (maximum 3200 mg/d)

– Adults are started at an initial dosage of 400 to 800 mg/d, with an increase of 400 to 800 mg every 2 days up to a maximum dosage of 3200 mg/d

• Open-treatment series have shown that gradual rufinamide titration with increases every 5 to 7 days, along with reductions in ineffective concomitant AEDs, may reduce AEs seen during titration in clinical trials, such as somnolence and dizziness

Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25]

VigabatrinVigabatrin

• Currently approved as monotherapy for the treatment of infantile spasms and as adjunctive therapy for adult patients with refractory complex partial seizures• MOA believed to be irreversible inhibition of γ-

aminobutyric acid transaminase (GABA-T)• Vigabatrin requires a Risk Evaluation and

Mitigation Strategy (REMS) to help manage the risk of permanent vision loss associated with use of the drug

Sabril® PI 2013.[26]

Krauss GL. Epilepsy Curr. 2009;9:125-129.[27]

Vigabatrin Carries a Boxed Warning for Vision LossVigabatrin Carries a Boxed Warning for Vision Loss• Vigabatrin causes permanent bilateral concentric visual

field constriction in 30% to 40% of patients

• Visual field defects typically occur within the first 2 years of therapy

• Mild to moderately severe and irreversible peripheral field loss

• Risk mitigation: registration, severe epilepsy, monitoring of favorable treatment response to justify continued therapy, perimetry testing required every 3 months

Sabril® PI 2013.[16]

Vigabatrin REMSVigabatrin REMS

Pellock JM, et al. Epilepsy Behav. 2011;22:710-717.[28]

Refractory Complex Partial

Seizures(n = 846)

Infantile Spasms

(n = 1500)Other

(n = 120)

Vigabatrin exposure

Exposed 308 390 53

Naive 493 992 57

Not reported 45 118 10

Dispensed vigabatrin 810 1470 117

Total patients in registry: 2473Total dispensed vigabatrin: 2397

AEDs in Clinical TrialsAEDs in Clinical Trials

• Brivaracetam

• Benzodiazepine

− Nasal sprays

− Sublingual (acute treatment)

• YKP3089

SummarySummary

• New AED therapies are emerging for treating drug-resistant epilepsy

• Novel AED mechanisms modulate sodium and potassium ion channels and AMPA receptors

• Individual patients may benefit from treatment with one of several new AEDs despite not tolerating or not responding to previous AEDs

AbbreviationsAbbreviationsAEs = adverse eventsAEDs = antiepileptic drugAMPA = α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidANCOVA = analysis of covarianceCI = confidence intervalCPS = complex partial seizuresCYP = cytochrome CBZ = carbazepineESL = eslicarbazepineFAS = full analysis setFDA = Food and Drug AdministrationGABA = gamma-aminobutyric acid ITT = intent to treatIV = intravenousKCNQ = potassium voltage-gated channel, KQT-like subfamily, member 1KM = kaplan-meier

LCM = lacosamideLGS = Lennox-Gastaut syndromeLOCF = last observation carried forwardMedDRA = Medical Dictionary for Regulatory ActivitiesmITT = modified intent to treatMOA = mechanism of actionOXC = oxcarbazepineOXC-MHD = oxcarbazepine monohydroxy derivativePK = pharmacokineticPGTC = primary generalized tonic-clonicPOS = partial-onset seizures REMS = risk evaluation and mitigation strategyTEAE = treatment-emergent adverse eventWBC = white blood cell

Abbreviations (cont)Abbreviations (cont)

1. Ng YT, Conry JA, Drummond R, et al. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011;77:1473-1481. 2. Stephen LJ, Brodie MJ. Pharmacotherapy of epilepsy: newly approved and developmental agents. CNS Drugs. 2011;25:89-107. 3. Elger C, Bialer M, Cramer JA, et al. Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia. 2007;48:497-504.

4. Jacobson MP, Pazdera L, Bhatia P, et al; study 046 team. Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study. BMC Neurology. 2015:15:46. 5. Sperling MR, Harvey J, Grinnell T, et al; 045 Study Team. Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a randomized historical-control phase III study based in North America. Epilepsia. 2015;56:546-555.

6. McCormack PL, Robinson DM. Eslicarbazepine acetate. CNS Drugs. 2009;23:71-79.

ReferencesReferences

7. Elger C, Halász P, Maia J, et al; BIA-2093-301 Investigators Study Group. Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study. Epilepsia. 2009;50:454-463. 8. Ben-Menachem E, Gabbai AA, Hufnagel A, et al. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res. 2010;89:278-285.

9. Vimpat® [package insert]. Smyrna, GA; UCB, Inc; 2015.

10. Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007;48:1308-1317. 11. Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia. 2010;51:958-967. 12. Halász P, Kälviäinen R, Mazurkiewicz-Beldzińska M, et al. Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial. Epilepsia. 2009;50:443-453.

References (cont) References (cont)

13. Chung S, Ben-Menachem E, Sperling MR, et al. Examining the clinical utility of lacosamide: pooled analyses of three phase II/III clinical trials. CNS Drugs 2010:24;1041-1054.

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