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Beth M. Silverstein, DONorth Shore University Hospital, North Shore–Long Island Jewish Health System, Manhasset, New York Abstract  Effective treatment of epilepsy remains a medical juggling act. Neu-
rologists must weigh effective control of seizure activity with patients’ medical  histories and comorbidities to create a treatment plan that often includes two or  more antiepileptic drugs (AEDs) with different mechanisms of action, increasing  the potential for significant adverse effects and also drug interactions. At the 2012  Efficacy, Safety, and Tolerability
Annual Meeting of the American Academy of Neurology, the results of a variety  With and Without Sodium-Channel
of recent clinical trials were presented on novel, third-generation AEDs, includ- Blockade
ing ezogabine; clobazam; lacosamide; eslicarbazepine acetate; and a once-daily,  extended-release formulation of topiramate.
lthough epilepsy therapy has controls subthreshold excitability, and azepine, lamotrigine, phenytoin, and improved greatly over recent suppresses seizures by opening neuronal oxcarbazepine. Understandably, sodium- years, 30%–40% of patients voltage-gated potassium channels.5 tive ezogabine therapy in patients with cal trials of adjunctive epilepsy therapy. tiepileptic drug (AED).1 In such patients, inadequately controlled partial-onset Non–sodium-channel blockers include more than one AED is used in attempts seizures was demonstrated in the phase II valproic acid, levetiracetam, pregabalin, Retigabine Efficacy and Safety Trials for and topiramate.
Since 1993, more than 10 AEDs have Partial Onset Epilepsy, RESTORE-16 and Two recent studies11,12 investigated the RESTORE-2.7 When compared with a effectiveness and safety of ezogabine ther- proic acid, carbamazepine, phenytoin, placebo group, patients taking 600, 900, apy in patients with partial-onset seizures phenobarbital, and the benzodiazepines.3 and 1,200 mg/d of this third-generation who were taking sodium-channel block- Novel drugs offer hope to patients who AED were significantly more likely to ers or non–sodium-channel blockers. continue to experience seizures after experience a 50% or greater reduction Participants in these studies were taking receiving multiple drugs or are unable to in 28-day total partial-onset seizure fre- tolerate their side effects. However, the ef- quency during a 12-week maintenance blocker but no other types of AEDs or at fectiveness of combination therapy using period and throughout an entire 16- to least one AED with a mechanism of ac- AEDs with separate mechanisms of action 18-week double-blinded treatment phase. tion other than sodium-channel blockade, The ezogabine group had significantly such as γ-aminobutyric acid (GABA) During the 64th Annual Meeting of the greater median reductions in 28-day to- American Academy of Neurology (AAN) tal partial-onset seizure frequency from calcium-channel interaction, and no in New Orleans, a number of posters were baseline than did the placebo group, sodium-channel blockers.
presented describing recent clinical stud- regardless of patient age, race, gender, or ies of novel AEDs, including ezogabine; seizure activity at baseline. Most adverse clobazam; lacosamide; eslicarbazepine events were mild to moderate, and use acetate; and a once-daily, extended-release of the drug general y was well tolerated.5 n EzogabinE
Treatment with ezogabine (known potassium channels and reduces neuro- as retigabine outside the United States) nal excitability.8 The drug is not likely to stabilizes the resting membrane potential, cause any pharmacokinetic interaction T H E N E U R O L O G Y R E P O R T   |   V o l u m e   5   N u m b e r   1
Beth M. Silverstein, DO  Recent Clinical Trials of Third-Generation Antiepileptic Drugs 
An integrated analysis on pooled Frequency of Adverse Events in Patients Taking Ezogabine vs Placebo Patients taking traditional
Patients taking non–
sodium-channel blockers
sodium-channel blockers
Ezogabine
Placebo
Ezogabine
Placebo
Adverse event
(n = 238)
(n = 106)
(n = 119)
(n = 77)
thrice-daily treatment with ezogabine or placebo, and then a titration phase of 2–6 weeks to achieve a target daily ezogabine dose of 600, 900, or 1,200 mg. Thereafter, a double-blind maintenance phase lasting 8 weeks (study 205) or 12 weeks (studies 301 study or a 3-week dosage-tapering phase.
Patients in study 205 were 16–70 years of age; those in studies 301 and 302 were 18–75 years of age. Patients in study 205 those in studies 301 and 302 were taking group (45%) were taking only one back- adverse events or serious adverse events up to three AEDs, with or without vagal ground AED.
were evident among patients with partial- stimulation. Al participants in these trials Efficacy. As reported by Brodie et al,11 onset seizures who were treated with
had experienced at least four partial-onset the median percent reduction in seizures ezogabine in conjunction with sodium- seizures over the past 28 days; they could over the double-blind treatment period channel blockers or AEDs having other not have been free of seizures for over 30 in all patients taking sodium-channel mechanisms of action. days (study 205) or more than 21 consecu- tive days (studies 301 and 302) during the versus 14% in the placebo group. Among efficacy with no apparent safety issues in baseline phase. Data on all patients given patients taking non–sodium-channel adults with drug-resistant partial-onset at least one dose of ezogabine or placebo blockers, the median percent reduction seizures who also were taking either tra- nel or non–sodium-channel blockers were ing ezogabine versus 21% in the placebo non–sodium-channel blocker AEDs.
Using data from these three trials, phase, the median percent reduction in n CLobazam
Brodie et al11 evaluated the effectiveness seizures for al patients in the sodium- of ezogabine as adjunctive therapy when channel blocker group was 46% in patients severe form of childhood-onset epilepsy given ezogabine versus 29% in those given characterized by frequent tonic, atonic, channel blockers or non–sodium-channel placebo. Among all patients using non– and atypical absence seizures; behavioral blockers to patients with partial-onset sodium-channel blockers, the reduction disturbances; cognitive dysfunction; and seizures. In a separate study, French et was 48% in all patients using ezogabine resistance to treatment. Treatment often al12 investigated the safety and tolerabil- focuses on attempts to improve injurious Safety and tolerability.  French and drop seizures (sudden tonic or atonic
patients. Among 1,240 patients included colleagues12 analyzed these same three fal s); these seizures are some of the most datasets for treatment-emergent adverse chal enging to control.14 Currently, cloba- blind population, 344 (28%) were using events, serious adverse events, and adverse zam, clonazepam, felbamate, lamotrigine, at least one sodium-channel blocker effects leading to withdrawal from the topiramate, and rufinamide have been with no non–sodium-channel blockers, study during ezogabine therapy.
Tolerability between the subgroups ministration (FDA) for the treatment of non–sodium-channel blocker without any generally was similar (Table 1).13 Ezo- experience seizures despite AED therapy.
graphics of the two groups were similar, lessened in some patients using sodium- although slightly more patients in the channel blockers that also induce glucuro- sodium-channel blocker group (59%) nyl transferases, such as carbamazepine ated with LGS in patients at least 2 years than in the non–sodium-channel blocker and phenytoin. Overal , no differences in of age.15 Its exact mechanism of action is T H E N E U R O L O G Y R E P O R T   |   S u m m e r   2 0 1 2  
Beth M. Silverstein, DO  Recent Clinical Trials of Third-Generation Antiepileptic Drugs 
unclear, but it probably involves potentia- tion of neurotransmission resulting from When compared with the age-matched receiving 0.25 mg/kg/d of clobazam from binding at the benzodiazepine site of the controls receiving placebo, patients week 12 to week 15.
Use with other AEDs. Renfroe and
exhibited a greater average and median col eagues19 studied the safety and efficacy Efficacy
percentage reduction in the frequency of clobazam used in conjunction with The double-blind, phase III Clobazam of drop seizures during the maintenance lamotrigine or valproate and the potential drome (CONTAIN) study16 compared cal y insignificant median reduction in three AEDs. Participants were screened three different daily doses of clobazam seizure frequency among patients ≥ 12 according to the same standards used by with placebo in patients ranging from 2 to < 17 years old who took 0.25 mg/kg/d Ng et al.18 The mean and median percent- to 60 years of age; LGS was documented of clobazam, possibly due to the small age weekly reductions in average drop and sample size (n = 8). The seizure reduction total seizure rates from baseline to the 12- graphic criteria. A total of 305 patients was dose-dependent, which was consis- were screened; 238 were randomized. tent with the overall CONTAIN results. for 72 patients receiving clobazam plus Further, seizure reduction in patients ≥ lamotrigine and 113 patients receiving fied ITT (mITT) population, and 177 17 years of age was consistent with that clobazam plus valproate.
individuals (mean age, 12.4 years; 60.5% observed in younger LGS patients. No male) completed the study. Patients in differences in the percentage reduction group, patients receiving all doses of the mITT population had baseline data, in seizure frequency were observed be- had received at least one clobazam dose, tween men and women or among racial had a greater mean percentage decrease in and had at least one seizure measurement or ethnic subgroups of patients receiving the average weekly rate of drop seizures, graphics and clinical characteristics were Sustained efficacy. Ng et al18 com-
valproate. The percentage decrease in total The study featured a 4-week baseline rienced by LGS patients given clobazam lamotrigine and clobazam plus valproate. period, a 3-week titration period, and or placebo between the first 4 weeks The percentages of patients experiencing a 12-week maintenance period. On day (weeks 4–7) and the last 4 weeks (weeks a ≥ 50%, ≥ 75%, and 100% decrease in –1, patients were stratified by weight and 12–15) of maintenance therapy. Patients the average weekly frequency of drop sei- randomly assigned to receive a target of experienced LGS before 11 years of age; zures general y increased with increasing 0.25 mg/kg/d (maximum, 10 mg/d), 0.5 their diagnoses were based on evidence clobazam dose. No dosage adjustment of of more than one type of generalized lamotrigine or valproate appeared to be kg/d (maximum, 40 mg/d) of clobazam seizure (including drop seizures for at needed during combination therapy.
or placebo. Use of clobazam resulted in least 6 months) and slow spike-and-wave significantly lower frequencies of drop electroencephalograms (< 2.5 Hz) and motrigine or valproate showed a general and total seizures linked to LGS that were multifocal spikes. Patients had to have pattern of adverse events similar to that dose-related. Improved drop seizure rates at least two weekly drop seizures over 4 of the overal population. Two patients experienced by LGS patients during the weeks and use up to three AEDs at stable treated concomitantly with 0.25 mg/ first 4 weeks of the CONTAIN 12-week dosages for at least 30 days before screen- ing. Final y, participants could not use perienced an unspecified adverse drug ing the last 4 weeks among patients using benzodiazepines chronically for ≥ 30 days reaction or pneumonia, and one patient Independence of efficacy on age,
Dropout rates for treatment groups had a jaw fracture or lobar pneumonia. gender, or race/ethnicity. Mitchell et potentially confounded these analyses. Among those treated concomitantly with
al17 studied the efficacy of clobazam in However, relative to placebo, the mean 0.25 mg/kg/d of clobazam and valproate, preventing drop attacks in LGS patients percentage reductions observed during pneumonia occurred in one patient, and of different ages, gender, and race (white, the first 4 weeks of maintenance therapy cyanosis, thrombocytopenia, vomiting, Asian, other) or ethnicity (Hispanic/Lati- persisted through the last 4 weeks for all and pneumonia were reported in two no vs non-Hispanic/Latino). The primary treated patients. The mean percentage re- patients. A drug administration error was endpoint was the percentage reduction in ductions in seizure frequency were higher reported in five patients using 0.5 mg/kg/d the average frequency of drop seizures per during the first 4 weeks of maintenance of clobazam with valproate; bronchopneu- week during maintenance therapy versus therapy in all groups. Still, differences monia, influenza, and lobar pneumonia the frequency at baseline. In addition, between treatment and placebo groups occurred in two patients taking 1.0 average weekly responder rates (ie, 25%, were statistical y significant for all pair- T H E N E U R O L O G Y R E P O R T   |   V o l u m e   5   N u m b e r   1
Beth M. Silverstein, DO  Recent Clinical Trials of Third-Generation Antiepileptic Drugs 
lobar pneumonia occurred in one patient extended-release topiramate once daily formulation. Further, there was no appar- and maintained on that dosage for 14 ent difference in the frequency or type of days before being downtitrated to 100 treatment-related adverse effects during n ExTEndEd-RELEasE
mg of extended-release topiramate once the 24 hours after subjects switched treat- TopiRamaTE
daily for 4 days, followed by 50 mg once ment, suggesting a minimal risk of de- Topiramate is an oral, twice-daily, daily for 4 days.
Steady-state pharmacokinetics.
the treatment of primary generalized Administration of extended-release topir- All adverse events occurring during treat- tonic-clonic seizures,20 partial-onset sei- amate once daily for 14 days provided ment with either immediate-release or zures,21–23 and seizures associated with an area under the curve (AUC) equiva- extended-release topiramate were mild.
LGS.24,25 The drug also is indicated for lent to the steady-state AUC observed prophylaxis of migraine headaches.26 An with immediate-release topiramate in Dose-Proportionality, Linearity, and
both groups.30 When compared with Tolerability of Extended-Release
immediate-release topiramate, once-daily Topiramate
sumably might increase patient adherence treatment with the extended-release for- to topiramate therapy and might lead to mulation of topiramate resulted in a lower proportionality and tolerability of a single more consistent plasma concentrations of peak plasma concentration (C max), a higher dose of extended-release topiramate. Thir- the drug.27–29 Two phase III trials currently trough plasma concentration (Cmin), and ty healthy fasting subjects were given 25, under way are evaluating the clinical less fluctuation in steady-state values. 50, 100, 200, or 400 mg of topiramate in ability assessments continued for 14 days partial-onset seizures (ClinicalTrials.gov period. The subjects were confined to the clinic for at least 10 hours before and 36 Steady-State Profiles and
Tolerability
with higher doses of the extended-release al30 and Lambrecht et al31 used a two-way treatment groups. In the extended-release to immediate-release group, subjects were Tolerability and maintenance of
started on 50 mg of extended-release steady-state plasma concentrations. dosing range. Cmax was dose-proportional
topiramate once daily, followed by 50-mg Lambrecht et al31 evaluated tolerability and when double-dose increases at higher increases in dosage every 4 days and then maintenance of steady-state plasma con- 200 mg once daily for 14 days. On day 15, centrations when subjects were switched mg) were compared, and it was linear over they were switched without a washout between immediate- and extended-release the entire dosing range. Treatment-related period to 100 mg of immediate-release forms of topiramate. Steady-state plasma adverse events general y increased with topiramate every 12 hours for 14 days. levels were maintained if the slope es- incremental doses; these events all were The dosage was then downtitrated to 50 timates for Cmin were not significantly mild to moderate.
mg of immediate-release topiramate every different from zero. The tolerability of 12 hours for 4 days and subsequently to both dosage forms were evaluated via n LaCosamidE
monitoring of adverse events, vital signs, In the immediate-release to extended- release group, subjects were given 25 mg of immediate-release topiramate every state plasma concentrations of topiramate dium channels.33 The oral forms of this 12 hours to start, followed by 50-mg/d were seen when subjects taking 200 mg/d third-generation AED are indicated for increases every 4 days and then 100 mg in two divided doses switched from the adjunctive therapy in treating partial- every 12 hours for 14 days. They were immediate-release formulation to 200 onset seizures in patients at least 17 years then immediately switched to 200 mg of mg once daily of the extended-release of age; the parenteral form is indicated T H E N E U R O L O G Y R E P O R T   |   S u m m e r   2 0 1 2  
Beth M. Silverstein, DO  Recent Clinical Trials of Third-Generation Antiepileptic Drugs 
as a short-term replacement when oral of adjunctive lacosamide, the patients three concomitant AEDs and underwent entered one of three open-label extension at least one post-dose seizure assessment. Efficacy according to concomitant
Safety and Efficacy
therapy. Versavel and col eagues38 evalu-
ated the safety and efficacy of adjunctive tive therapy with lacosamide. At greater bazepine acetate based on the AED used lacosamide in patients with refractory than 1, 3, and 5 years, 75%, 53%, and 18% concomitantly. AEDs most commonly focal epilepsy in a multicenter, prospec- of patients, respectively, were exposed to used were carbamazepine (58.7%), la- tive, open-label, observational study. They lacosamide; the decrease with time was motrigine (23.5%), valproic acid (23.5%), recruited 105 patients with epilepsy who due to premature drug discontinuations and topiramate (16.7%). were not control ed on monotherapy. The and study completion because lacosamide patients were assessed at months 3, 6, and became commercial y available. Main rea- of eslicarbazepine acetate once daily sig- 12; endpoints were seizure freedom for sons for drug discontinuation were lack of nificantly reduced seizure frequency when 6 months, mean seizure reduction rate efficacy (28%), consent withdrawal (12%), compared with placebo. No significant > 50%, and study withdrawal due to lack and treatment-emergent adverse effects interactions between type of AED used (11%). Common adverse effects related and treatment effect were found. How- Thus far, 50 patients have been assessed to treatment were dizziness (37%), head- at 6 months. In al , 80% had formerly tried ache (19%), nasopharyngitis (16%) and more than one concomitant AED, the diplopia (15%). Adverse effects leading to investigators could not assess the impact amide to their antiepileptic regimen. The discontinuation in ≥ 0.5% of patients were of particular drug combinations.
investigators observed a significant reduc- dizziness (1.7%) and convulsion (0.9%).
Time to adverse events. Sperling et
For 1-, 3-, and 5-year completers, al39 performed an analysis to review the each month, with the monthly median the median percent seizure reduction timing and incidence of adverse events rate decreasing from 4.0 to 1.2 seizures from baseline was 52%, 60%, and 65%, during eslicarbazepine acetate therapy. (P < 0.0001). Altogether, 42% of patients respectively; the ≥ 50% responder rate The dose of the drug was titrated per responded to lacosamide, and 13 of these was 53%, 60%, and 65%; the ≥ 75% re- patients achieved remission for the last 3 sponder rate was 26%, 31%, and 41%; and AED in response to treatment-emergent months. Eight patients entered remission the seizure-free rate was 3.0%, 2.5% and adverse reactions were permitted. The since starting lacosamide; patients using a 1.6%. Treatment with lacosamide for up weekly incidence and time to onset of sodium-channel blocker were as likely as to 8 years general y was wel tolerated and adverse events for patients completing associated with reduced seizure frequency the 14-week titration and maintenance periods were calculated. The studies were similar in overall design but had different quently in patients taking lacosamide with n EsLiCaRbazEpinE aCETaTE
titration schedules and starting doses.
During the first 2 weeks of therapy, the those using other AEDs with lacosamide. eslicarbazepine, is a third-generation AED most common adverse events reported In al , 13 patients reported a transitory related to carbamazepine and oxcarbaze- pine.37 It was granted approval in Europe diplopia, and nausea. In each dosing ziness and somnolence) that occurred as adjunctive therapy for partial-onset group, some 30% of all adverse effects seizures in patients ≥ 18 years of age; the occurred during week 1, with the inci- Lacosamide appeared to be an effective FDA has not yet approved the marketing dence declining during later weeks. After and wel -tolerated adjunctive AED that of this novel prodrug for a voltage-gated 4 weeks of therapy, the incidence of new may be used with both sodium-channel sodium-channel blocker.
blockers and other AEDs. The tolerability among patients receiving eslicarbazepine of this drug is improved with slow dose Efficacy and Time to Adverse Events
escalation and eventual reduction of the double-blind, placebo-control ed phase acetate-related adverse events most likely II studies38,39 evaluated once-daily use of would start when therapy began; over the Long-Term Therapy
eslicarbazepine acetate given as adjunctive ensuing weeks, the incidence of new ad- Rosenfeld and others36 studied the therapy to 790 patients with partial-onset verse events was similar among the active open-label use of lacosamide to treat seizures. Patients in the ITT popula- adults with partial-onset seizures for tion received at least one 400-, 800-, or this analysis was conducted post hoc with- 1,200-mg dose of eslicarbazepine acetate out formal statistical testing, and adverse sponding phase II/III double-blind trial or placebo added to a regimen of one to events were not evaluated by severity.
T H E N E U R O L O G Y R E P O R T   |   V o l u m e   5   N u m b e r   1
Beth M. Silverstein, DO  Recent Clinical Trials of Third-Generation Antiepileptic Drugs 
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