New Antiepileptic Medications

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Presentation transcript:

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

Evolving 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 Content Slide Layout: TEXT

Recent AEDs Drug Company FDA Approval 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 Adjunctive therapy for POS and PGTC seizures in patients ≥ 12 y Retigabine/ Ezogabine (Potiga®) GSK/Valeant Adjunctive therapy for POS in patients ≥ 18 y Rufinamide (Banzel®) Adjunctive therapy for LGS in patients ≥ 1 y Vigabatrin (Sabril®) 2009 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) 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) 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) Mean Decrease in Seizure Rate, % (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]

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. 2015:15:46.[4]; Sperling MR, et al. Epilepsia. 2015;56:546-55.[5]

Eliscarbazepine acetate Eslicarbazepine Chemical Structure 5% Oxcarbazepine Eliscarbazepine acetate R(-)-licarbazepine S(+)-licarbazepine Shares dibenzazepine nucleus with CBZ and OXC, but with 5- carboxamide substitute Primarily converted to S-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]

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

Eslicarbazepine Phase 3 Treatment-Emergent Adverse Events Treatment-Emergent Adverse Events With ≥ 10% Incidence Rates BIA-2093-301 BIA-2093-302 Placebo (n = 102) ESL 400 mg/d (n = 100) ESL 800 mg/d (n = 98) (n = 96) (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 7.1 Somnolence 6.0 17.0 15.6 16.8 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] 10

Cumulative Exit Rate at 112 Days (KM Estimate), %; 95% CI Eslicarbazepine Monotherapy Conversion Trial Kaplan–Meier-Estimated 112-Day Exit Rate 65.3% lower confidence limit of historical controls 15.6 (8.1-28.7) Cumulative Exit Rate at 112 Days (KM Estimate), %; 95% CI 12.8 (7.5-21.5) Jacobson MP, et al. BMC Neurology. 2015:15:46. Jacobson MP, et al. BMC Neurology. 2015:15:46.[4]

(R)-2-acetzamido-N-benzyl-3-methoxypropionamide Lacosamide (R)-2-acetzamido-N-benzyl-3-methoxypropionamide 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(+) configuration is active Molecular weight: 250.3 Water solubility: 27 mg/mL

Lacosamide Pharmacokinetic 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]

ITT – indirect comparison of results Lacosamide: Median Percent Reduction in Seizure Frequency Per 28 Days: Baseline to Maintenance, Per Randomized Dose n = 359 n = 267 n = 466 n = 202 ITT – indirect comparison of results between 3 studies Median Reduction, % 21 37 38 † 10 26 39 40 36 * 35 20 30 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. 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 Adverse Event (%) MedDRA Preferred Term Placebo n = 364 Lacosamide 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 17 Diplopia 2 6 10 Vomiting 3 Fatigue 15 Vision blurred Coordination abnormal The most common adverse events (AEs) seen in the lacosamide pivotal trials are listed on the slide. The most frequent treatment-emergent adverse events (TEAEs) occurring in lacosamide-treated patients during the treatment phase (i.e., titration plus maintenance) were:1 dizziness (31% of lacosamide-treated patients versus 8% of placebo-treated patients) headache (13% versus 9%) nausea (11% versus 4%) diplopia (11% versus 2%). Most of the reported AEs were mild to moderate in intensity.2 The incidence of severe AEs (SAEs) was 10.4% for all lacosamide-treated patients versus 4.7% of placebo-treated patients.2 The most frequently reported drug-associated SAE was dizziness (3.7%), which occurred at a higher incidence in patients randomised to the lacosamide 600 mg/day† group (9.4%). The incidence of severe dizziness was similar in patients in the lacosamide 200 mg/day (1.9%) and 400 mg/day (2.3%) groups.2 • The maximum recommended daily dose for lacosamide is up to 400 mg/day. Source: 1. 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 (12): 1041–1054. 2. Gil-Nagel A, Biton V, Fountain NB, et al. The safety and tolerability of lacosamide in randomized, double-blind, placebo-controlled phase II/III clinical trials. Poster presented at the 28th International Epilepsy Congress, Budapest 2009. 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]

Pooled Phase 2/3 Trial Data Lacosamide Optimizing Combination Therapy ≥ 50% Responder Rate in Patients Taking ≥ 1 Concomitant Sodium-channel Blocking AEDs (ITTm Population*) Pooled Phase 2/3 Trial Data ≥ 50% Responder Rate, % ‡ n = 337 n = 244 n = 393 n = 142 ‡ † Overall, 82% (1,077/1,308; safety population) of patients were using at least one concomitant traditional sodium-channel blocking AED.1 In both the pooled pivotal trial population and in the group of patients treated with traditional sodium-channel blocking AEDs, patients treated with lacosamide 200–600 mg/day showed higher ≥50% responder rates compared to placebo-treated patients (lacosamide 400 mg/day and 600 mg/day, p<0.01).1 The median percent reduction in seizure frequency per 28 days was significantly greater for the lacosamide 200–600 mg/day treatment groups compared with placebo-treated patients in both the pooled pivotal trial population and in the group of patients treated with concomitant traditional sodium-channel blocking AEDs.1 Source: 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 (12): 1055–1068. *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]

Infusion duration 30 min, N = 40 n (%) Lacosamide Infusion AEs MedDRA Preferred Term Infusion duration 30 min, N = 40 n (%) Headache 3 (8) Dizziness Diplopia 2 (5) Nausea Somnolence 4 (10) Fatigue 0 (0) Abdominal pain, upper WBC urine positive Infusion reactions Adverse event rates were low and consistent with that seen with oral lacosamide. Importantly, AEs do not increase with shorter infusion durations From Krauss AAN 2008. Krauss G, et al. Epilepsia. 2010;51:951-957.[17]

Lacosamide Monotherapy Conversion Trial Kaplan–Meier-Estimated 112-Day Exit Rate 65.3% lower confidence limit of historical controls Kaplan-Meier Predicted Exit Percentage 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 Wechsler RT, et al. Epilepsia. 2014;55:1088-1098.[18]

5'-(2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl-6'(1'H)-one 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 Placebo Perampanel 2 mg Perampanel 4 mg Perampanel 8 mg (P < .001*) (P = .013*) Median Percentage Change (Reduction) in Seizure Frequency Percentage of Patients (P = NS*) n = 184 n = 180 n = 172 n = 169 Median percentage reductions in seizure frequency per 28 days (ITT)– double-blind phase vs baseline Percentage of patients experiencing ≥ 50% reduction in seizure frequency (ITT) – maintenance (LOCF) period vs baseline * = vs placebo Krauss GL, et al. Neurology. 2012;78:1408-15.[19]

Perampanel Treatment-Emergent Adverse Events Incidence of TEAEs (Safety Population) Patients, n (%) Placebo n = 185 2 mg/d n = 180 4 mg/d n = 172 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) 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 11 (6.1) 3 (1.8) Nasopharyngitis 3 (1.6) 7 (3.9) 9 (5.2) Gait disturbance 2 (1.1) 1 (< 1) 2 (1.2) Krauss GL, et al. Neurology. 2012;78:1408-15.[19]

Perampanel for the Treatment of Refractory PGTC Seizures French JA, et al. Neurology. 2015. [Epub ahead of print].[20]

Retigabine/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]

Retigabine Dose-Ranging Trial for POS Primary Efficacy Results Intent-to-Treat Population Partial-seizure Frequency, % Change in Total Monthly Retigabine* *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 Other Headache 10.4* 11.0-17.0 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 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 Tonic-atonic seizures Total seizures Reduction, % ≥ 50% Responders, % 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 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 Seizures 50% Responder Rate 14‡ 9 4.7 16* 12† 10 20 30 40 Placebo 200 mg/d 400 mg/d 800 mg/d 1600 mg/d Responder Rate, % 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 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 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]

Refractory Complex Partial Seizures Vigabatrin REMS 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: 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) YKP3089

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 MedDRA = Medical Dictionary for Regulatory Activities mITT = 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

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