Effectiveness of adjunctive low-dose clobazam in adults with focal drug-resistant epilepsy and incomplete response to cenobamate: A real-world study.

In randomised controlled trials, adjunctive cenobamate (CNB) has been shown to reduce seizure frequency in patients with drug-resistant focal epilepsy. Studies conducted in real-world settings provide valuable complementary data to further characterise the drug's profile. To assess the efficacy, retention and tolerability of adjunctive cenobamate (CNB), and to identify factors that might predict these outcomes in the clinical treatment of focal epilepsies. This multicentre, retrospective cohort study included all patients who began CNB treatment between October 2020 and April 2023 at seven participating epilepsy centres. Baseline and follow-up data were collected from patients' medical records, covering clinical characteristics and outcome data such as seizure frequency, dosing of CNB, physician-assessed Clinical Global Impression of Change, treatment-emergent adverse events (TEAEs), CNB retention and reasons for discontinuation. A total of 234 patients [mean age 40.7 ± 14 years, median 40 years, range 11-82 years; five adolescents under 18 years; 99 (42.3%) males] were analysed. The mean epilepsy duration at study entry was 23.2 ± 14.5 years (median 21 years, range 0.75-63 years), with the average age of epilepsy onset being 17.5 ± 13.0 years (median 17 years, range 0.1-71 years). The patients were taking a mean of 2.6 ± 0.8 (median 3) anti-seizure medications (ASMs) before starting CNB, and had failed a mean of 6 ± 3.3 (median 6) of further ASMs in the past. CNB exposure ranged from 5 to 1162 days, amounting to a total exposure time of 264.7 years. The retention rate was 92.6% at 3 months, 87.2% at 6 months and 77.8% at 12 months. At 3 months, 52.6% achieved a 50% seizure reduction, with 14.5% reporting seizure freedom; by 12 months, 47.7% maintained a 50% response rate and 11.9% were seizure-free. No significant differences in responder rates were observed based on sex, aetiology, seizure localisation, number of ASMs or target dose. The mean maximum CNB dose was 236.7 ± 97.4 mg (median 200 mg, range 12.5-450 mg), with 28 patients (12.0%) titrated up to 400 mg or above. During CNB treatment, 43.6% of patients were able to discontinue, and a further 24.4% were able to reduce the dose of a concomitant ASM. During CNB treatment, 144 patients (61.5%) experienced TEAEs. The most common TEAEs were sedation (n = 84, 35.9%), dizziness (n = 58, 24.8%) and ataxia (n = 23, 9.8%). CNB showed a relatively high and clinically useful 50% responder rate of 47.7% and an overall retention of 77.8% at 1 year. We were unable to identify specific predictors for response and retention, indicating that CNB may be beneficial for patients with a history of multiple failed ASMs, a high number of concomitant ASMs and any localisation or aetiology of focal epilepsy.

Early antiseizure response to cenobamate (200 mg/day) in focal drug-resistant epilepsy: a retrospective single-center analysis

Background: Cenobamate (CNB) is an anti-seizure medication (ASM) approved in 2021 in Europe for adjunctive treatment of focal-onset seizures in adults who were not adequately controlled with at least two previous ASMs.Methods: seizure outcome, treatment-emergent adverse events, neuropsychological profile, and blood levels of CNB and concomitant ASM were analyzed in a real world setting in two different Italian epilepsy centers in the context of CNB early access program. All patients performed a general cognitive evaluation, while 32 patients underwent the administration of a battery of neuropsychological tests at baseline and 6 months after CNB treatment. We performed CNB quantification in plasma in 31 patients at different doses in the range of 100–400 mg/day (65 measures).Results: we enrolled 54 patients with a median age of 27.9 years. The mean follow-up was 10.7 months. Most (91%) completed the efficacy analysis. At last follow-up visit, a 69.5% median seizure reduction was registered. Thirty-two patients (59.2%) had a ≥50% reduction of seizures that was ≥75% in 20 (42.0%) cases, whilst 10 (20.2%) patients were seizure-free. The most common adverse events were somnolence (53.1%), dizziness (28.1%) and diplopia (12.5%). The correlation between CNB dose and plasma concentration, revealed a significant linear correlation (r = 0.86, p < 0.0001), and there was a significant difference in mean plasma concentration/dose administered ratio (C/D ratio) between patients taking or not at least one inducer (0.10 ± 0.04 [(μg/mL)/(mg/day)]; n = 47 vs. 0.13 ± 0.05 [(μg/mL)/(mg/day)]; n = 18, p = 0.04). CNB dose was inversely correlated (r = −0.31, p = 0.02) to the C/D ratio of Carbamazepine blood levels. and positively correlated (r = 0.74, p < 0.0001) with an increased plasma concentration of the active Clobazam metabolite N-desmethylclobazam. General Anxiety Disorder-7 showed a significant improvement of score from baseline evaluation of 6.82 to follow-up 6 months evaluation of 4.53 (p = 0.03).Conclusion: In this real-world study, we registered a clinically meaningful reduction in seizure frequency after CNB administration in most patients along with a good tolerability profile. CNB treatment is correlate to a reduction in symptom severity of anxiety score. Plasma levels measurements confirm that CNB acts both as “victim” and as “perpetrator” of drug-drug interactions.

Cenobamate (CNB) has demonstrated remarkable efficacy in the treatment of drug-resistant focal epilepsy (FE). However, its role in other epilepsy types - such as drug-resistant generalized epilepsies (GEs), combined generalized and focal epilepsies (CGFEs), and developmental and epileptic encephalopathies (DEEs) - remains poorly explored. This article assesses the current evidence of CNB efficacy in these often complex and challenging patient populations. A case report is presented detailing a 22-year-old male with drug-resistant epilepsy with myoclonic-atonic seizures (EMAtS) who achieved seizure freedom on CNB. A systematic literature review was conducted to evaluate CNB's efficacy in GEs, CGFEs, and DEEs, summarizing seizure outcomes, adverse events (AEs), and dose-response relationships. The case report highlights a patient achieving 18 months of sustained seizure freedom and improved quality of life with tapering of concomitant antiseizure medications (ASMs). The systematic review included 32 patients from six studies. Overall, 59.4 % achieved a ≥ 50 % seizure reduction, and 9.4 % attained seizure freedom. Subgroup analysis showed ≥50 % reduction in 50 % of patients with Lennox-Gastaut syndrome (LGS) and 80 % with Dravet syndrome (DS), with seizure freedom rates of 20 % in DS and 50 % in epilepsy with eyelid myoclonia (EEM). AEs, primarily sedation and fatigue, were reported in 74 % of patients, while 31.25 % reduced or tapered off ASMs. CNB demonstrates potential efficacy in managing seizures across drug-resistant epilepsy syndromes, extending its established use beyond FE. Further prospective trials are needed to validate these findings and optimize dosing strategies.

Cenobamate (CNB) is an effective antiseizure medication, though its mechanisms of efficacy remain incompletely understood. We assessed changes in cortical responses to transcranial magnetic stimulation (TMS) following CNB treatment. We recruited people with drug-resistant focal epilepsy scheduled to start add-on CNB in a tertiary epilepsy center. We performed TMS coupled with electromyography (EMG) and electroencephalography (EEG) at baseline, at 100 mg/day and at the maximum tolerated or minimum effective dose. Participants were categorized as responders (≥50% seizure reduction) or nonresponders. We used linear mixed models and cluster-based permutation tests to assess CNB effects on resting motor thresholds (rMTs), intracortical inhibition and the amplitude, mean field power and event-related spectral perturbation of TMS-evoked EEG potentials (TEPs). For TMS measures that were significantly affected by CNB dose (p < 0.05), we assessed differences between responders and non-responders and correlations with seizure frequency. Twenty-eight participants completed the study (16 females; median age, 50 years). rMT (p < 0.01) increased and cortical silent period (CSP) lengthened (p = 0.03) with increasing CNB dose. These changes did not differ between responders and nonresponders, nor did they correlate with reduced seizure frequency. Short- and long-interval intracortical inhibition, as well as all TEP parameters, remained unchanged. While CSP lengthening may merely reflect higher stimulation intensities, rMT increases align with CNB's suggested modulation of sodium channels. rMT changes that are independent of clinical response suggest that sodium channel effects do not fully account for the therapeutic efficacy of CNB. We used magnetic brain stimulation in people with epilepsy to find out how the antiseizure medication cenobamate affects brain activity. As its dose increased, cenobamate raised the stimulation strength required to activate a muscle, known as the resting motor threshold (rMT). These changes did not predict a reduction in seizures. This suggests that cenobamate's effectiveness involves more than its effects on mechanisms linked to the rMT.

The cenobamate-clobazam interaction- evidence of synergy in addition to pharmacokinetic interaction

ABSTRACTBackgroundVagus Nerve Stimulation (VNS) is an effective neuromodulatory treatment for drug‐resistant epilepsy (DRE), but many patients still experience uncontrolled seizures. These patients, who are highly refractory, may benefit from novel anti‐seizure medications (ASM). This study evaluates the effectiveness of cenobamate (CNB) in patients previously or currently treated with VNS.MethodsWe reviewed the medical history of all patients treated with VNS at Ghent University Hospital and HUB‐Hôpital Erasme Brussels from 1995 to 2024. Patients who received CNB after ≥ 12 months of VNS therapy were included. Mean monthly seizure frequency was assessed before VNS, after VNS, and post‐CNB initiation.ResultsAmong 620 patients treated with VNS between March 1995 and November 2023, 54 were additionally treated with CNB after a median VNS duration of 9 years. With VNS, seizure frequency data were available for 52 patients. Of these, 13 (25%) achieved a ≥ 50% reduction in seizure frequency at maximum follow‐up, but none became seizure‐free. After CNB addition (median dose 200 mg, median follow‐up 10 months), 24/54 (44.4%) experienced a ≥ 50% reduction in seizures. 6/54 patients (11.1%) reported seizure freedom for a median of 26 weeks. In 20/54 patients (37%), the number of ASMs was reduced. 7/54 (13%) discontinued CNB because of side effects, with fatigue being the most common, in 23/54 patients (42.6%).ConclusionsFor DRE patients treated with VNS who could benefit from further improvement in seizure control, adding CNB is useful. In our cohort, over one‐third of patients experienced a meaningful improvement in seizure frequency with this recently marketed ASM.

Refractory epilepsy remains a major therapeutic challenge, affecting approximately one third of patients with persistent seizures despite treatment with multiple antiseizure medications (ASMs). Cenobamate (CNB), a novel ASM, has shown promising efficacy in both clinical trials and real-world settings. This observational study aimed to evaluate the efficacy, tolerability, and retention of CNB in adults with drug-resistant focal-onset seizures in routine clinical practice. A cross-sectional analysis was conducted on 40 patients treated with CNB at Santa Lucía University Hospital between 2022 and 2024. Seizure frequency, CNB discontinuation, adverse effects, and concomitant ASMs were assessed at 1, 3, and 6 months. We found a significant reduction in mean monthly seizures, from 48.4 at baseline to 12.1 at 6 months ( P =0.0001). At 6 months, 48% of patients had a ≥50% seizure reduction, and 27% were seizure-free. In addition, CNB treatment was associated with a significant reduction in Defined Daily Doses and the number of concomitant ASMs. A 95% retention rate was observed among patients after 6 months on CNB treatment. Only 2 patients discontinued CNB, neither due to adverse effects. Reported adverse effects were mild to moderate, with somnolence (13%) and dizziness (10%) being the most common. These findings reinforce CNB as a valuable treatment option for patients with focal-onset drug-resistant epilepsy, supporting its integration into clinical practice. Further research is needed to evaluate long-term outcomes and its potential role as a first-line therapy.

Cenobamate's effect on mood and seizure frequency.

To evaluate the efficacy of cenobamate (CNB) in adults with focal epilepsy based on the number of previous lifetime antiseizure medications (ASMs). Twenty patients receiving add-on treatment with CNB with <6 lifetime ASMs were retrospectively compared to 20 Patients with >10 ASMs and approximately the same age. Efficacy was assessed at 3, 6, and 12 months following CNB initiation. In patients with <6 lifetime ASMs, seizure frequency significantly decreased at 3, 6, and 12 months (p = 0.03, 0.027, 0.048, respectively), while no significant changes were observed in the >10 lifetime ASM group. The median percentage of seizure reduction in the <6 lifetime ASMs group was 58 % at 3 months, 50 % at 6 months, and 92 % at 12 months, compared to 36 %, 50 %, and 42 % in the >10 lifetime ASM group. The seizure-free rate was significantly higher in the <6 lifetime ASMs group at all-time points (p < 0.01), despite a lower median daily dose of CNB in this group. There was a trend toward higher responder rates at 12 months in the <6 lifetime ASMs group, again despite the lower median daily dose of CNB. This study highlights greater efficacy of CNB in patients with <6 lifetime ASMs, showing a significantly higher seizure-free rate and greater seizure reduction compared to those with >10 lifetime ASMs. Despite lower overall response in the latter group, CNB treatment still provided meaningful benefits in highly drug-resistant epilepsy.

IntroductionEpilepsy poses significant management challenges, particularly in patients with refractory epilepsy where conventional antiseizure medications (ASMs) are ineffective. Cenobamate (CNB), a recently approved third-generation ASM, has shown unprecedented efficacy as an adjunctive therapy in clinic-based practice. However, to date, its use by office-based neurologists in Germany remains relatively limited. One reason for this is its perceived complexity and false perception as a medication of last resort. This study focuses on the logistics of German care pathways, CNB titration, and ASM combinations in a first cohort of office-based outpatients. It also gives a glimpse into which ASMs are being used in the office-based setting in comparison to population and clinic-based data sources.MethodsThe cohort comprised 55 patients from two office-based outpatient practices (Niedergelassene) in Berlin (n = 25) and Hamburg (n = 30). All patients had a history of refractory epilepsy despite optimal treatment with existing ASMs. Patients were initiated on CNB from the month of approval (June 2021) to March 2023. Data on prior ASM usage were collated alongside clinical data, which included seizure frequency and drug load reduction outcomes to March 2025.ResultsPrior to CNB initiation, patients at both office-based practices had similar levels of 1–2 concurrent ASMs (Berlin 80%; Hamburg 77%). The most common ASMs were voltage-gated sodium channel blockers (VGSC), Levetiracetam (LEV)/Brivaracetam (BRV) synaptic vesicle protein 2A (SV2A) inhibitors, and Perampanel (PER). CNB titration was configured into a quarterly office-based outpatient schedule. All patients had seizure reductions in-line with published and real-world evidence, and were compliant.Discussion and conclusionCNB is a valuable adjunctive therapy suitable for refractory epilepsy outpatients attending office-based neurologists. A slow titration schedule helped mitigate most side effects. Despite differences to clinic-based practice, in office-based outpatient practice CNB can be broadly used. It can be prescribed to patients on conventional therapy who are still having seizures and have failed two or more other ASMs. By reporting experiences of CNB titration, seizure, and drug load reduction outcomes in office-based neurology, this study will give German office-based outpatient neurologists evidence to support both CNB and other third-generation ASM use in their practice.

Approximately one-third of people living with epilepsy are unable to obtain seizure control with the currently marketed antiseizure medications (ASMs), creating a need for novel therapeutics with new mechanisms of action. Cenobamate (CBM) is a tetrazole alkyl carbamate derivative that received US Food and Drug Administration approval in 2019 for the treatment of adult partial onset (focal) seizures. Although CBM displayed impressive seizure reduction in clinical trials across all seizure types, including focal aware motor, focal impaired awareness, and focal to bilateral tonic-clonic seizures, the precise mechanism(s) through which CBM exerts its broad-spectrum antiseizure effects is not known. Experimental evidence suggests that CBM differentiates itself from other ASMs in that it appears to possess dual modes of action (MOAs); that is, it predominately blocks persistent sodium currents and increases both phasic and tonic γ-aminobutyric acid (GABA) inhibition. In this review, we analyze the preclinical efficacy of CBM alongside ASMs with similar MOAs to better understand the mechanism(s) through which CBM achieves such broad-spectrum seizure protection. CBM's preclinical performance in tests, including the mouse 6-Hz model of treatment-resistant seizures, the chemoconvulsant seizure models of generalized epilepsy, and the rat hippocampal kindling model of focal epilepsy, was distinct from other voltage-gated sodium channel blockers and GABAA modulators. This distinction, in light of its proposed mechanism(s) of action, provides insight into the impressive clinical efficacy of CBM in the adult patient with focal onset epilepsy. The results of this comparative reverse translational analysis suggest that CBM is a mechanistically distinct ASM that offers an important advancement in drug development for treatment of therapy-resistant epilepsy.

ObjectiveThis study investigated early, real‐world outcomes with cenobamate (CNB) in a large series of patients with highly drug‐resistant epilepsy within a Spanish Expanded Access Program (EAP).MethodThis was a multicenter, retrospective, observational study in 14 hospitals. Inclusion criteria were age ≥18 years, focal seizures, and EAP authorization. Data were sourced from patient clinical records. Primary effectiveness endpoints included reductions (100%, ≥90%, ≥75%, and ≥50%) or worsening in seizure frequency at 3‐, 6‐, and 12‐month visits and at the last visit. Safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation.ResultsThe study included 170 patients. At baseline, median epilepsy duration was 26 years and median number of seizures/month was 11.3. The median number of prior antiseizure medications (ASMs) and concomitant ASMs were 12 and 3, respectively. Mean CNB dosages/day were 176 mg, 200 mg, and 250 mg at 3, 6, and 12 months. Retention rates were 98.2%, 94.5%, and 87% at 3, 6, and 12 months. At last available visit, the rate of seizure freedom was 13.3%; ≥90%, ≥75%, and ≥50% responder rates were 27.9%, 45.5%, and 63%, respectively. There was a significant reduction in the number of seizures per month (mean: 44.6%; median: 66.7%) between baseline and the last visit (P < 0.001). Responses were maintained regardless of the number of prior or concomitant ASMs. The number of concomitant ASMs was reduced in 44.7% of patients. The cumulative percentage of patients with AEs and AEs leading to discontinuation were 68.2% and 3.5% at 3 months, 74.1% and 4.1% at 6 months, and 74.1% and 4.1% at 12 months. The most frequent AEs were somnolence and dizziness.SignificanceIn this highly refractory population, CNB showed a high response regardless of prior and concomitant ASMs. AEs were frequent but mostly mild‐to‐moderate, and few led to discontinuation.

Background: Cenobamate (CNB) is an anti-seizure medication (ASM) approved for the treatment of drug-resistant focal epilepsy in adults. Notwithstanding significant proof of efficacy, real-world pharmacokinetics (PK) data are lacking, particularly regarding sex-based variations and the effect of concomitant ASMs. This exploratory study aimed to investigate the PK profile of CNB in responder adults with drug-resistant focal epilepsy and assess potential relationship with concomitant ASMs and clinical variables. Methods: We enrolled 17 patients receiving add-on CNB. The concentration-to-dose ratio (C/D), incremental slope (ΔC/ΔD), and dose-to-concentration AUC were calculated. Enrolled individuals were stratified into three exposure clusters (low, medium, and high). Univariate ANOVA was used to explore associations between PK parameters, clinical variables and concomitant ASMs. Results: Sex appeared to be associated with AUC cluster classification (p = 0.026), showing females predominating in the high-exposure group. A nonlinear dose-concentration relationship emerged from the ΔC/ΔD analysis, showing steeper slopes at low doses (12.5–50 mg), great variability at higher doses (100–200 mg), and a negative slope in some individuals. Higher CNB concentrations were observed in patients co-treated with lacosamide, while concomitant topiramate was associated with lower exposure. Carbamazepine and valproate showed non-significant trends consistent with their known enzyme-inducing and inhibiting properties. Conclusions: PK of CNB appears highly variable and seems to be influenced by sex and concomitant ASMs. These findings highlight the importance of therapeutic drug monitoring and individualized titration strategies to optimize efficacy and safety in clinical practice. These results should be regarded as exploratory and hypothesis-generating due to the small and monocentric sample size and need to be confirmed in larger, multicenter cohorts.

Background and ObjectivesTo evaluate long-term efficacy (percent seizure frequency reduction and responder rates), safety, and tolerability of adjunctive cenobamate (CNB) in an open-label extension (OLE) of the randomized, double-blind, placebo-controlled study.MethodsPatients (aged 18–70 years) with uncontrolled focal seizures despite treatment with 1–3 antiseizure medications who completed the 18-week double-blind study (n = 360) could enter the OLE, where they underwent a 2-week blinded conversion to CNB (target dose, 300 mg/d; min/max, 50/400 mg/d).ResultsThree hundred fifty-five patients were included in the OLE safety population (265 originally randomized to CNB, 90 originally randomized to placebo), and 354 were included in the OLE modified intent-to-treat population. As of July 2019, 58.9% of patients (209/355) were continuing CNB treatment and 141 had discontinued, including 16.6% (59/355) because of lack of efficacy, 8.7% (31/355) because of withdrawal by patient, and 7.6% (27/355) because of adverse events. The median (range) duration of OLE exposure was 53.9 (1.1–68.7) months. Retention rates at 12, 24, 36, and 48 months were 83%, 71%, 65%, and 62%, respectively. Median percent seizure frequency reduction over baseline increased with each 6-month OLE interval, up to 76.1% at months 43–48. Among observed patients, 16.4% (36/220) achieved 100% and 39.1% (86/220) achieved ≥90% seizure reduction during >36–48 months. Among the initial OLE modified intent-to-treat population, 10.2% of patients (36/354) achieved 100% and 24.3% (86/354) achieved ≥90% seizure reduction during >36–48 months. Similar to the double-blind study, adverse events (AEs) included dizziness, somnolence, fatigue, and headache. Serious AEs occurred in 20.3% of patients (72/355).DiscussionLong-term efficacy, including 100% and ≥90% seizure reduction, was sustained during 48 months of CNB treatment, with 71% retention at 24 months. No new safety issues were identified. These results confirm the findings of the double-blind study and support the potential long-term clinical benefit of CNB.Classification of EvidenceThis study provides Class IV evidence that oral CNB 50–400 mg/d is effective as an adjunctive treatment for the long-term management of patients with uncontrolled focal seizures previously treated with 1–3 ASMs.Trial Registration InformationClinicalTrials.gov NCT01866111 (clinicaltrials.gov/ct2/show/results/NCT01866111).