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THINK … EFFICACY, TOLERABILITY & LONG TERM

Key data on cenobamate

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Pubblished: 2025-04-01

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A data-driven look at the impact of cenobamate

“I tried every medication that existed; however, nothing would minimise, let alone, stop the seizures”1

This statement highlights a common experience for doctors and their patients with epilepsy: the ongoing search for effective therapies that can provide lasting relief from seizures. Finding the right treatment regimen often involves navigating a complex landscape of treatment options1.  

Cenobamate, an adjunctive treatment for focal-onset seizures in adults, offers an interesting mechanism of action with its dual antiseizure activity. It promotes the inactivated state of voltage-gated sodium channels, blocking persistent sodium currents, and acts as a positive allosteric modulator of GABAA receptors at a site distinct from benzodiazepines.2  

The following data deepdive will give you an overview of cenobamate's potential in achieving the seizure freedom and how real-world experience reflects the learnings from clinical trials.

  • Cenobamate treatment has been associated with considerable seizure freedom rates in two pivotal trials enrolling 659 patients.3  
    Efficacy of cenobamate was demonstrated in studies C013 and C017,  two randomized, double- blind, placebo-controlled, multicenter studies (treatment lengths ≤ 18 weeks) in adults with uncontrolled focal  seizures despite taking 1–3 ASMs.4  
    Study C013 reported seizure freedom in 28.3% of participants administered 200 mg/day of cenobamate (vs 8.8% of those taking placebo)5; Study C017 demonstrated seizure freedom in 21% of participants taking 400 mg/day of cenobamate (vs 1% with placebo).5

  • The results observed in clinical trials are similar in real-world settings, with higher dosages needed to achieve seizure freedom2. 

  • Pietrafusa et al 2023: A retrospective study conducted at two Italian epilepsy centers evaluated the effectiveness of cenobamate (CNB) as an add-on treatment in 54 adult patients (median age: 27.9 years) with drug-resistant focal epilepsy. All patients received cenobamate through Angelini Pharma's Early Access Program (EAP) between 2020 and 2022. Seizure outcome, treatment-emergent adverse events, neuropsychological profile, and blood levels of CNB and concomitant ASMs were analyzed.3

    Study population: All patients treated with add-on CNB, aged ≥18 years and diagnosed with drug-resistant focal epilepsy were included. The patients were taking in median of 3 ASMs and had been treated with median of 9 ASMs. 29.6% had vagal nerve stimulation therapy 35.2% had failed epilepsy surgery.3

    Baseline period: the 4 weeks before starting CNB. Efficacy outcomes were evaluated at 3, 6, 9 and 12 months after the introduction of CNB. The primary efficacy endpoint was the percentage change in
    monthly baseline seizure frequency at the last follow-up visit (LFV). The seizure frequency up to the LFV was calculated as the number of seizures recorded during the treatment with CNB (including both the
    titration and maintenance phase), divided by the number of days from the initiation of CNB to the LFV. The result was multiplied by 28 to obtain a monthly frequency.3

    Outcome: Following CNB administration, a clinically meaningful reduction in seizure frequency was observed in most patients: 42.0% experienced a >75% reduction in baseline seizure frequency, and 20.2% achieved seizure freedom.3 At LFV the median dose of CNB was 201.8 mg/day. Nearly 60% of patients were able to reduce or withdraw one or more concomitant ASMs. None of the patients experiences significant alterations in QTc interval and no significant blood test alterations were registered. CNS-related side effects were the most reported. Ataxia and diplopia were more frequent with concomitant SCB in treatment regimen, likely explained by pharmacodynamic interaction. Many cases were resolved by lowering the number or dose of concomitant ASMs. In this real-world study cenobamate demonstrated to be tolerable and it provided sustained, clinically meaningful seizure reduction.3

  • Spanish Expanded Access Program (EAP) between August 2020 - June 2022: A multicenter, retrospective, observational study investigated real-world outcomes with cenobamate in a large cohort of patients (n=170) with highly drug-resistant epilepsy.2

    Study population and baseline: Patients were over 18 years old, diagnosed with focal onset seizures and considered highly drug-resistant. The patient population had been treated in median of 12 ASMs and were taking in median 3 concomitant ASMs, of which lacosamide (35.9%), brivaracetam (35.3%), carbamazepine (34.1%), and clobazam (31.8%) were the most used. Many of the patients would have been ineligible for inclusion in the clinical trials based on their number of concomitant ASMs, their psychiatric comorbidities, or their recent history of status epilepticus.2

    Mean CNB dosages/day were 176 mg, 200 mg, and 250 mg at 3, 6, and 12 months. The study data suggests that many patients experienced clinically relevant seizure reductions at cenobamate dose of 100 or 200 mg/day , but it seems that higher dosages were needed to achieve seizure freedom, particularly in the long term.2

    This study showed that 63% of patients achieved a ≥50% reduction in seizure frequency, and 13.3% of patients were seizure-free at their last visit.2 The percentage, type, and severity of adverse events in this study were similar to those reported in clinical trials. The most frequent adverse events were somnolonce and dizziness. No body skin rashes were reported and there were no cases of drug reaction with eosinophilia and systemic symptoms (DRESS) or hypersensitivity syndrome (HSS). A particular tendency for a dose reduction or discontinuation of concomitant SCBs and clobazam was observed, similarly to earlier findings in post-hoc analysis of a CNB clinical trial C021. Efficacy of cenobamate in this study did not depend on the number of concomitant ASMs.2

    • A post-hoc analysis observed high retention rates on cenobamate during the clinical development program. An estimated 80% of patients remained on treatment at the end of 1 year and 72% at 2 years. After titration, retention remained high, with cenobamate doses ≥100 mg/day; concomitant anti-seizure medications did not impact retention.7
    • Most patients continued to benefit from cenobamate and tolerated the treatment well over the course of a year, as demonstrated by the 87% retention rate at 12 months in the Spanish Expanded Access Program (EAP) study.2

    • Real-world experience with cenobamate indicates a consistent safety profile. The percentage, type, and severity of Adverse Events (AEs) in studies were similar to those reported in clinical trials.2 Since cenobamate's launch in 2020, there have been no confirmed cases of DRESS with cenobamate.8
    • AEs were frequent but mostly mild-to-moderate2. In clinical trial C013, C017 and C021 most adverse events were mild to moderate. Most adverse events leading to study drug discontinuation in C013 and C017 occurred during titration, and adverse events were more frequent in patients receiving higher doses.9 The most commonly reported AEs in real-world studies were somnolence, dizziness, ataxia and diplopia.3,10,11
    • Behavioural and psychiatric adverse events did not appear to be a significant problem.9
      In clinical trials, there were low rates of behavioural and psychiatric adverse events.9
      In a post-hoc analysis of pooled populations of patients with uncontrolled focal seizures, occurrence of cognitive and psychiatric TEAEs was low in patients during double-blind and open-label treatment with adjunctive cenobamate for up to 7 years in three phase 2 and phase 3 clinical trials. During open-label treatment, fewer than 2 % of patients discontinued adjunctive treatment due to these AEs, demonstrating that adjunctive cenobamate treatment was not a major contributor to cognitive and psychiatric TEAEs and may therefore be a useful alternative in patients who are experiencing, or who may be at risk for, cognitive and psychiatric TEAEs.12

▼ Detta läkemedel är föremål för utökad övervakning.

Ontozry® (cenobamat) 12,5 mg odragerad tablett samt 25 mg, 50 mg, 100 mg, 150 mg och 200 mg filmdragerade tabletter. Rx F. ATC-kod: N03AX25 - antiepileptika, övriga antiepileptika. Indikation: Ontozry är indicerat som tilläggsbehandling av fokala anfall, med eller utan sekundär generalisering hos vuxna patienter med epilepsi, som inte kontrollerats tillräckligt trots tidigare behandling med minst två antiepileptika. Kontraindikationer: Överkänslighet mot den aktiva substansen eller mot något hjälpämne, ärftligt kort QT-syndrom. Varningar: Patienter ska instrueras att uppsöka läkare om tecken på självmordstankar/självmordsbeteende uppstår, samt om tecken och symptom på läkemedelsreaktion med eosinofili och systemiska symtom (DRESS) inträffar. Innehåller laktos. Cenobamat kan minska exponeringen av substanser som metaboliseras via CYP3A4, CYP2B6 samt öka exponeringen av substanser som metaboliseras via CYP2C19. Cenobamat rekommenderas inte till fertila kvinnor som inte använder preventivmedel eller vid amning. MAH: Angelini Pharma S.p.A.  Lokal kontakt: Angelini Pharma Nordics, nordic.medinfo@angelinipharma.com. Datum för senaste översyn av SPC: 2/2025. För pris och ytterligare information, se www.fass.se.

ASM = anti-seizure medication, CNB = cenobamate, SCB = sodium-channel blocker, AE = adverse event, TEAE = treatment-emergent adverse event

  1. Reeder S, Foster E, Vishwanath S et al. Experience of waiting for seizure freedom and perception of machine learning technologies to support treatment decision: A qualitative study in adults with recent onset epilepsy. Epilepsy Res. 2023;190:107096
  2. Villanueva V, Santos-Carrasco D, Cabezudo-García P et al. Real-world safety and effectiveness of cenobamate in patients with focal onset seizures: Outcomes from an Expanded Access Program. Epilepsia Open. 2023;8(3):918-929.
  3. Pietrafusa N, Falcicchio G, Russo E et l. Cenobamate as add-on therapy for drug resistant epilepsies: effectiveness, drug to drug interactions and neuropsychological impact. What have we learned from real word evidence? Front Pharmacol. 2023;14:1239152.
  4. Sperling MR, Abou-Khalil B, Aboumatar S et al. Efficacy of cenobamate for uncontrolled focal seizures: Post hoc analysis of a Phase 3, multicenter, open-label study. Epilepsia. 2021 Dec;62(12):3005-3015. 
  5. Chung SS, French JA, Kowalski J et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology 2020; 94(22): e2311-e2322
  6. Krauss GL, Klein P, Brandt C et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. Lancet Neurol 2020; 19(1): 38-48.
  7. Sander JW, Rosenfeld WE, Halford JJ et al. Long‐term individual retention with cenobamate in adults with focal seizures: pooled data from the clinical development program. Epilepsia. 2022 Jan;63(1):139-49.
  8. Ferrari L, Rosenfeld WE, Kamin M. A global update on cenobamate based on real-world experience in over 100 000 patients. Epilepsia. 2024 Mar 6. Epub ahead of print.
  9. Steinhoff BJ, Rosenfeld WE, Serratosa JM et al. Practical guidance for the management of adults receiving adjunctive cenobamate for the treatment of focal epilepsy-expert opinion. Epilepsy Behav. 2021 Oct;123:108270
  10. Chen S, Fang W, Zhao L et al. Safety assessment of cenobamate: real-world adverse event analysis from the FAERS database. Frontiers in Pharmacology. 2024 Mar 15;15:1369384.
  11. Rodríguez‐Uranga JJ, Sanchez-Caro JM, Ramchandani RH. Treatment simplification to optimize cenobamate effectiveness and tolerability: A real‐world retrospective study in Spain. Epilepsia Open. 2024 May 27.
  12. Krauss GL, Chung SS, Ferrari L et al. Cognitive and psychiatric adverse events during adjunctive cenobamate treatment in phase 2 and phase 3 clinical studies. Epilepsy Behav. 2024 Feb;151:109605

MAT-SE-0007-P Feb 2025

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