New developments in epilepsy: focus on cenobamate


Cenobamate received Health Canada authorization last year as adjunctive therapy for patients with partial-onset seizures who are not adequately controlled with conventional therapies. The drug acts as a sodium channel blocker through selection inhibition of the persistent sodium current, and as a GABAA receptor modulator.

Approval was based on the results of two phase II trials in patients with partial-onset seizures. A dose-response study (N=437) reported a median decrease in seizure frequency of 35.5% in the cenobamate 100 mg/day group, 55.0% in the 200 mg/day group and 55.0% in the 400 mg/day group versus 24.0% with placebo (Krauss et al. Lancet Neurol 2020;19:38-48). The responder rate (≥50% reduction) during the maintenance phase was 40% in the cenobamate 100 mg group, 56% in the 200 mg group and 64% in the 400 mg group versus 25% with placebo.

The second study (N=222) evaluated the efficacy of adjunctive cenobamate 200 mg/day in patients with refractory partial-onset seizures despite treatment with other anti-seizure medications (ASM) (Chung et al. Neurology 2020;94:e2311-e2322). The median reduction in seizures was 55.6% with cenobamate 200 mg/day versus 21.5% with placebo. The responder rate (>50% reduction) was 50.4% with cenobamate compared to 22.2% with placebo.

Long-term data from the pivotal trial by Krauss and colleagues (n=355) were presented at the American Epilepsy Society annual meeting, held December 1-5, 2023, in Orlando, Florida (Nisman et al. AES 2023;P1.31). Results were stratified according to seizure subtype: focal aware motor (FAM) (20.6%), focal impaired awareness (FIA) (89.6%), or focal to bilateral tonic-clonic (FBTC) (36.6%). A >12-month duration of 100% seizure reduction was achieved by 29.8% (FAM), 30.8% (FIA), and 65.7% (FBTC) of patients. A ≥24-month duration of 100% seizure reduction was achieved by 21.3%, 27.4% and 59.6%, respectively. A ≥90% seizure reduction occurred in 31.6%, 32.1% and 61.1%, respectively. Over 48-60 months of treatment, the rate of’ >90% seizure reduction increased to 46.3%, 44% and 74.7% for the three subtypes.

Real-world efficacy results
Two new efficacy analyses for cenobamate were presented at the recent American Academy of Neurology (AAN) annual meeting. A pharmacy claims database analysis of patients with focal epilepsy examined epilepsy-related hospitalizations and emergency room visits after an adjunctive ASM was initiated (Urban et al. AAN 2024;S29.003). Add-on medications included cenobamate, brivaracetam, clobazam, eslicarbazepine, lacosamide, lamotrigine, levetiracetam and perampanel. Overall, there were 170.6 in-patient days/100 patient-years and 41.0 ER visits/100 PY. The number of in-patient days and ER visits was significantly lower when cenobamate was used compared to all other adjunctive agents examined. The increase versus cenobamate in in-patient days ranged from 1.7/100 PY for lamotrigine to 6.4/100 PY for lacosamide. For ER visits, differences versus cenobamate ranged from 2.0/100 PY with brivaracetam to 8.8/100 PY for levetiracetam.

A separate analysis of the same database examined the efficacy of adjunctive therapy in patients with refractory seizures post-epilepsy surgery (Pellinen et al. AAN 2024;P8.004). The number of in-patient days was significantly lower with cenobamate compared to most other adjunctive therapies. Differences versus cenobamate ranged from 0.004/100 PY with lamotrigine to 10.3/100 PY for lacosamide. The lowest number of in-patient days was seen with eslicarbazepine. Cenobamate was associated with the lowest number of ER visits. The increase in ER visits relative to cenobamate ranged from 3.4/100 PY with brivaracetam to 9.2/100 PY with levetiracetam.

Also noteworthy was a recent network meta-analysis of adjunctive ASMs in focal epilepsy (Zhou et al. AES 2023;P3.284). The highest 100% responder rate was seen with cenobamate (odds ratio 8.64 vs. eslicarbazepine; OR 11.68 vs. rufinamide; OR 8.82 vs. zonisamide). There was a significant risk of all-cause drop-out for all ASMs except cenobamate and levetiracetam.

Cenobamate dosing and administration
Cenobamate is initiated at a dose of 12.5 mg once-daily for two weeks, titrated to 25 mg/day in weeks 3-4, 50 mg/day in weeks 5-6, 100 mg/day in weeks 7-8, 150 mg/day in weeks 9-10, and to the usual maintenance dose of 200 mg/day thereafter. If a higher dose is required, the dose may be increased in 50 mg-increments every two weeks to a maximum daily dose of 400 mg.

As cenobamate is added to the ASM regimen, it is generally recommended to adjust the dosing of the concomitant ASMs to minimize pharmacokinetic and/or pharmacodynamic interactions. Cenobamate inhibits the P450 2C19 isoenzyme that metabolizes ASMs such as phenytoin, clobazam and phenobarbital. This interaction increases the plasma concentration of phenytoin, phenobarbital and the active metabolite of clobazam. As a result, it is recommended that the dosing of these ASMs be reduced during cenobamate titration. For example, it is recommended that the dose of clobazam be reduced 5-10 mg/day at cenobamate initiation for patients on clobazam <40 mg/day, or to reduce clobazam by 10-20 mg/day in patients on >40 /mg/day of clobazam. Consensus recommendations on ASM dose adjustments during treatment with cenobamate were published by Smith and colleagues (Neurol Ther 2022;11:1705-1720; free full text at

Dose reduction of concomitant ASMs was shown to increase tolerability and retention in a phase III trial of cenobamate (Rosenfeld et al. Epilepsia 2021;62:3016-3028). Treatment response rates were similar after concomitant ASM dose reduction. Moreover, 24.6% of patients were able to discontinue one or more ASMs entirely during treatment with cenobamate. A post-hoc analysis of phase III data reported that earlier and larger ASM dose reductions were made as clinicians gained experience with the drug (Ferrari et al. AAN 2024;P8.003).

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