New Antiepileptic Medications Drug Profiles Efficacy Safety and

New Antiepileptic Medications Drug Profiles, Efficacy, Safety, and Tolerability

Evolving Epilepsy Therapy • Treatments – First-generation AEDs § 1930 -1980 s – Second-generation AEDs § 1984 -2006 – Third-generation AEDs § 2006 -today – Orphan AEDs • Needs – Tolerability – Safety – Added efficacy

Recent AEDs FDA Approval Drug Company Indication Clobazam (Onfi®) Lundbeck 2011 Adjunctive therapy for LGS in patients ≥ 2 y Eslicarbazepine (Aptiom®) Sunovion (Sepracor + Dainippon) 2013 2015 Monotherapy or adjunctive therapy for POS Lacosamide (Vimpat®) UCB Pharma 2008 2014 Monotherapy or adjunctive therapy for POS in patients ≥ 17 y Perampanel (Fycompa™) Eisai 2012 2015 Adjunctive 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 2013 Monotherapy for infantile spasms Adjunctive therapy for CPS in patients ≥ 10 y

Clobazam • 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) – T 1/2 = 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) • 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]

Mean Decrease in Seizure Rate, % Clobazam (cont) (95% CI, 51. 5 -85. 1) P <. 0001 80 Drop seizures 70 Total (drop and nondrop) seizures 60 (95% CI, 24. 9 -57. 6) P =. 0120 41. 2 50 40 30 20 10 0 68. 3 (95% CI, 33. 4 -65. 4) P =. 0015 49. 4 65. 3 (95% CI, 47. 2 -83. 5) P <. 0001 45. 3 (95% CI, − 3. 6 to 27. 8) 34. 8 12. 1 (95% CI, 17. 2 -52. 5) P =. 0414 (95% CI, 28. 1%-62. 5% P =. 0044 9. 3 (95% CI, − 7. 6 to 26. 3) Placebo (n = 57) Low Dosage (n = 53) Ng YT, et al. Neurology. 2011; 77: 1473 -1481. [1] Medium Dosage (n = 58) High Dosage (n = 49)

Eslicarbazepine • 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: 46. [4]; Sperling MR, et al. Epilepsia. 2015; 56: 546 -55. [5]

Eslicarbazepine Chemical Structure • Shares dibenzazepine nucleus with CBZ and OXC, but with 5 carboxamide substitute Oxcarbazepine 5% • Primarily converted to S-licarbazepine • 4% converted to R-licarbazepine via oxcarbazepine Eliscarbazepine acetate R(-)-licarbazepine S(+)-licarbazepine Stephen LJ, et al. CNS Drugs. 2011; 25: 89 -107. [2]; Elger C, et al. Epilepsia. 2007; 48: 497 -504. [3]

Eslicarbazepine Pivotal Trial Results Percent Reduction in Seizure Frequency and 50% Responder Rate 50 45 40 35 Median Relative Reduction in Seizure Frequency * ** 50 45 40 35 * † † 30 % Responder Rate 25 25 20 20 15 15 10 10 5 5 0 0 Study 301 n = 402 Study 302 n = 393 Placebo Study 303 n = 252 ESL 400 mg Study 301 n = 402 ESL 800 mg *P <. 001; †P <. 05. Mc. Cormack PL, et al. CNS Drugs. 2009; 23: 71 -79. [6] Study 302 n = 393 ESL 1200 mg Study 303 n = 252

Eslicarbazepine Phase 3 Treatment-Emergent Adverse Events With ≥ 10% Incidence Rates BIA-2093 -301 BIA-2093 -302 Placebo ESL 400 mg/d ESL 800 mg/d (n = 102) (n = 100) (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 0 2. 0 7. 1 4. 0 8. 3 14. 9 2. 0 6. 0 9. 2 17. 0 15. 6 16. 8 Diplopia Somnolence • Other AEs (NR in 301): nausea (range 4. 0 -11. 9), abnormal coordination (5. 0 -12. 9), vomiting (3. 0 -12. 9) NR = not reported. Incidence rates are for approved doses. 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 Trial Kaplan–Meier-Estimated 112 -Day Exit Rate Cumulative Exit Rate at 112 Days (KM Estimate), %; 95% CI 70 65. 3% lower confidence limit of historical controls 60 50 40 30 15. 6 (8. 1 -28. 7) 20 12. 8 (7. 5 -21. 5) 10 0 ESL 1200 mg Neurology. 2015: 46. ESL 1600 mg Jacobson MP, et al. BMC Neurology. 2015: 46. [4]

Lacosamide • 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. 3 Water solubility: 27 mg/m. L

Lacosamide Pharmacokinetic Profile • Predictable and doseproportional 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 Vimpat® PI 2015. [9] • 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

Lacosamide: Median Percent Reduction in Seizure Frequency Per 28 Days: Baseline to Maintenance, Per Randomized Dose Median Reduction, % 60 50 40 SP 667 a SP 754 b SP 755 c ITT – indirect comparison of results between 3 studies * 35 30 20 10 0 21 21 † † † 39 37 36 † † 40 38 LCM 400 mg/d n = 466 LCM 600 mg/d n = 202 26 10 Placebo n = 359 LCM 200 mg/d n = 267 *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. 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]

Lacosamide Safety and Tolerability: Pooled Pivotal Trial Data Adverse Events Occurring (≥ 10%) During the Treatment Phase Lacosamide Adverse Event (%) Med. DRA Preferred Term Placebo n = 364 200 mg/d n = 270 400 mg/d n = 471 600 mg/d n = 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. Chung S, et al. CNS Drugs. 2010; 24: 1041 -1054. [13] Gil-Nagel A, et al. IEC 2009. Poster 508. [14]

Lacosamide Optimizing Combination Therapy ≥ 50% Responder Rate, % ≥ 50% Responder Rate in Patients Taking ≥ 1 Concomitant Sodium-channel Blocking AEDs (ITTm Population*) 80 70 60 50 40 30 20 10 0 Pooled Phase 2/3 Trial Data ‡ † ‡ 44. 3 48. 6 34. 8 23. 1 Current Therapy +Current Therapy + Current Therapy Placebo LCM 200 mg/d LCM 400 mg/d + LCM 600 mg/d n = 337 n = 244 n = 393 n = 142 *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 placebo The 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]

Lacosamide Infusion AEs Med. DRA Preferred Term Infusion duration 30 min, N = 40 n (%) 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]

Kaplan-Meier Predicted Exit Percentage Lacosamide Monotherapy Conversion Trial Kaplan–Meier-Estimated 112 -Day Exit Rate Lacosamide 400 mg/d 100 80 65. 3% lower confidence limit of historical controls 60 40 20 0 30 32. 3 Primary Assessment Secondary Assessment Patients meeting ≥ 1 exit criterion during the Lacosamide Maintenance Phase, FAS Wechsler RT, et al. Epilepsia. 2014; 55: 1088 -1098. [18] Patients meeting ≥ 1 exit criterion, withdrawals due to a TEAE, and withdrawals due to lack of efficacy during the Lacosamide Maintenance Phase, FAS

Perampanel Selective Antagonist for the AMPA Subtype of Ionotropic Glutamate Receptors Chemical Structure 5'-(2 -cyanophenyl)-1'-phenyl-2, 3'bipyridinyl-6'(1'H)-one

Perampanel Study 306 Median Percentage Reduction in Seizure Frequency and 50% Responder Rate Perampanel 2 mg Median Percentage Change (Reduction) in Seizure Frequency Placebo Perampanel 4 mg Perampanel 8 mg Responder Rate Percentage of Patients 40 35 28. 5 30 (P =. 013*) 20. 6 25 20 34. 9 (P <. 001*) 17. 9 (P = NS*) 15 10 5 0 n = 184 n = 180 n = 172 n = 169 Median percentage reductions in seizure frequency per 28 days (ITT)– double-blind phase vs baseline * = vs placebo Krauss GL, et al. Neurology. 2012; 78: 1408 -15. [19] n = 184 n = 180 n = 172 n = 169 Percentage of patients experiencing ≥ 50% reduction in seizure frequency (ITT) – maintenance (LOCF) period vs baseline

Perampanel Treatment-Emergent Adverse Events Incidence of TEAEs (Safety Population) Patients, n (%) 4 mg/d n = 172 Placebo n = 185 2 mg/d n = 180 8 mg/d n = 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) 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) 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) TEAEs in ≥ 5% (any treatment group) Upper respiratory tract infection Krauss GL, et al. Neurology. 2012; 78: 1408 -15. [19]

Perampanel for the Treatment of Refractory PGTC Seizures Perampanel (N = 81) 80 64. 2 60 39. 5 40 20 0 P =. 0019 -40 -38. 4 -60 -100 30. 9 12. 3 P <. 0001 -20 -80 Placebo (N = 81) -76. 5 Median % Change From Baseline in PGTC Seizure Frequency 50% PGTC Seizure Responder Rate French JA, et al. Neurology. 2015. [Epub ahead of print]. [20] Tonic Clonic Seizure-free Rate

Retigabine/Ezogabine • Novel MOA with activation of neuronal M-current mediated by KCNQ (Kv 7) voltage-gated potassium channelsa • Half-life of 8 to 11 hoursa • 3 x-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]

Retigabine Dose-Ranging Trial for POS Primary Efficacy Results Intent-to-Treat Population Change in Total Monthly Partial-seizure Frequency, % Retigabine* 0 Placebo 600 mg/d 900 mg/d 1200 mg/d -10 -20 -30 -13. 1 -23. 4† -40 -29. 3† -35. 2 -50 *P <. 047 for overall difference across retigabine 300, 600, and 1200 mg/d arms †P <. 001 for overall difference across all treatment arms Porter RJ, et al. Neurology. 2007; 68: 1197 -1204. [23]

Retigabine Dose-ranging Trial for Partial-Onset Seizures Adverse Events 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 10. 4* 11. 0 -17. 0 Other Headache 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. Porter RJ, et al. Neurology. 2007; 68: 1197 -1204. [23]

Retigabine 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]

Rufinamide • 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 sodiumdependent 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 20 11. 7 Reduction, % 10 1. 4 0 -10 -20 -32. 7 -40 -42. 5 -50 Rufinamide Placebo ≥ 50% Responders, % Tonic-atonic seizures 45 40 35 30 25 20 15 10 5 0 Total seizures 42. 5 31. 1 16. 7 10. 9 Rufinamide Placebo Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010: 753 -55. [25]

Rufinamide Tolerability Adverse events occurring in patients treated with rufinamide vs placebo Rufinamide 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 Adverse Event Placebo Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010: 753 -55. [25]

Rufinamide for Adjunctive Treatment of Partial Seizures 50% Responder Rate, % 40 30 20 10 0 16* 12† 14‡ 9 4. 7 Placebo 200 mg/d 400 mg/d 800 mg/d 1600 mg/d Rufinamide *P =. 027; †P =. 012; ‡P =. 016. Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010: 753 -55. [25]

Rufinamide Additional 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 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]

Vigabatrin • 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 γaminobutyric 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 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 REMS Refractory Complex Partial Seizures (n = 846) Infantile Spasms (n = 1500) Other (n = 120) Exposed 308 390 53 Naive 493 992 57 Not reported 45 118 10 810 1470 117 Vigabatrin exposure Dispensed vigabatrin Total patients in registry: 2473 Total dispensed vigabatrin: 2397 Pellock JM, et al. Epilepsy Behav. 2011; 22: 710 -717. [28]

AEDs in Clinical Trials • Brivaracetam • Benzodiazepine − Nasal sprays − Sublingual (acute treatment) • YKP 3089

Summary • 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

Abbreviations AEs = adverse events AEDs = antiepileptic drug AMPA = α-Amino-3 -hydroxy-5 -methyl-4 -isoxazolepropionic acid ANCOVA = analysis of covariance CI = confidence interval CPS = complex partial seizures CYP = cytochrome CBZ = carbazepine ESL = eslicarbazepine FAS = full analysis set FDA = Food and Drug Administration GABA = gamma-aminobutyric acid ITT = intent to treat IV = intravenous KCNQ = potassium voltage-gated channel, KQT-like subfamily, member 1 KM = kaplan-meier

Abbreviations (cont) LCM = lacosamide LGS = Lennox-Gastaut syndrome LOCF = last observation carried forward Med. DRA = Medical Dictionary for Regulatory Activities m. ITT = modified intent to treat MOA = mechanism of action OXC = oxcarbazepine OXC-MHD = oxcarbazepine monohydroxy derivative PK = pharmacokinetic PGTC = primary generalized tonic-clonic POS = partial-onset seizures REMS = risk evaluation and mitigation strategy TEAE = treatment-emergent adverse event WBC = white blood cell

References 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: 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. Mc. Cormack PL, Robinson DM. Eslicarbazepine acetate. CNS Drugs. 2009; 23: 71 -79.

References (cont) 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 partialonset 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 partialonset 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) 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; 10411054. 14. Gil-Nagel A, Biton V, Fountain N, et al. The safety and tolerability of lacosamide in randomized, double-blind, placebo-controlled phase II/III trials. Poster presented at: 28 th International Epilepsy Congress; June-July 2009; Budapest, Hungary. P 508. 15. Sake JK, Hebert D, Isojärvi J, et al. A pooled analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant antiepileptic drugs. CNS Drugs. 2010; 24: 1055 -1068. 16. Isojärvi J, Hebert D, Doty P, et al. Evaluation of lacosamide efficacy and safety as adjunctive therapy in patients receiving traditional sodium channel blocking AEDs. Poster presented at: 9 th European Congress on Epileptology; June-July 2010; Rhodes, Greece. P 230. 17. Krauss G, Ben-Menachem E, Mameniskiene R, et al; SP 757 Study Group. Intravenous lacosamide as short-term replacement for oral lacosamide in partial-onset seizures. Epilepsia. 2010; 51: 951 -957.

References (cont) 18. Wechsler RT, Li G, French J, et al; ALEX-MT Study Group. Conversion to lacosamide monotherapy in the treatment of focal epilepsy: results from a historical-controlled, multicenter, double-blind study. Epilepsia. 2014; 55: 1088 -1098. 19. Krauss GL, Serratosa JM, Villanueva VE, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology. 2012; 78: 14081415. 20. French JA, Krauss GL, Wechsler RT, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: A randomized trial. Neurology. 2015 [Epub ahead of print]. 21. Luszczki JJ. Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions. Pharmacol Rep. 2009; 61: 197 -216. 22. Bialer M, Johannessen SI, Levy RH, et al. Progress report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT IX). Epilepsy Res. 2009; 83: 1 -43. 23. Porter RJ, Partiot A, Sachdeo R, et al. Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures. Neurology. 2007; 68: 1197 -204.

References (cont) 24. Potiga® [package insert]. Research Triangle Park, NC: 2015. 25. Krauss GL, Darnley S. Rufinamide. In: Wyllie E, et al, ed. Wyllie's Treatment of Epilepsy: Principles and Practice. 5 th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010: 753 -755. 26. Sabril® [package insert]. Deerfield, IL: Lundbeck; 2013. 27. Krauss GL. Evaluating risks for vigabatrin treatment. Epilepsy Curr. 2009; 9: 125 -129. 28. Pellock JM, Faught E, Sergott RC, et al. Registry initiated to characterize vision loss associated with vigabatrin therapy. Epilepsy Behav. 2011; 22: 710 -717.