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C017: A multicentre, double-blind, randomised, placebo-controlled, dose-response trial of cenobamate as adjunctive therapy in subjects with focal onset seizures, with optional open-label extension⁷

• Pivotal Phase IIb, multinational, multicentre, randomised, double-blind, placebo-controlled (efficacy and safety) study
• Primary endpoint: Percentage of patients achieving ≥50% reduction from baseline in focal seizure frequency (during the 12-week maintenance phase of the double-blind treatment period) when adding placebo or ONTOZRY^® to an ongoing regimen of 1-3 ASMs (SOC)
• One of the secondary endpoints: Percentage change from baseline in seizure frequency per 28 days by seizure type (focal aware with motor component, focal with impaired awareness, or focal to bilateral tonic-clonic seizures)

C021: An open-label, multicentre, safety and pharmacokinetic study of YKP3089 as adjunctive therapy in subjects with partial onset seizures⁸

• During the development of cenobamate, 3 cases of drug reaction with eosinophilia and systemic symptoms (DRESS) occurred. To mitigate the rate of DRESS, a start-low, go-slow approach was studied: C021 is an ongoing, large multicentre Phase III, open-label study to assess the long-term safety of adjunctive ONTOZRY^® when initiating ONTOZRY^® at a low dose (12.5 mg/day) and titrating every 2 weeks. At data cut-off, 1,347 patients were enrolled; 1,339 patients received ≥1 treatment dose. After 12 months, patients benefiting from treatment may continue on ONTOZRY^® at the discretion of the investigator. Safety assessments included reported AEs. Monthly reviews of all AEs in the clinical database via standardised MedDRA queries for hypersensitivity and DRESS were performed. In addition, physical examinations to identify signs of hypersensitivity were performed every 2 weeks during the first 4 months of treatment, at Year 1, and yearly thereafter

Footnotes

*In patients who had focal onset seizures uncontrolled despite treatment with at least one ASM within the past 2 years and taking 1-3 concomitant ASMs at stable doses for at least 4 weeks prior to screening. In the randomly assigned population at baseline, median number of previous ASMs taken at any time before the start of the study was 3 (range 2-4); these might or might not have been ongoing during the study. 74% (n=322/437) of patients were taking 2-3 concomitant ASMs during the study. Post hoc analysis of median percentage change in 28-day focal seizure frequency, mITT-M population (all randomly assigned adult patients who completed the 6-week titration phase, took at least one dose of study drug in the maintenance phase, and had maintenance phase seizure data). Median percentage change in 28-day focal seizure frequency in patients taking ONTOZRY^® 400 mg/day was: focal aware motor seizures, n=20/82, 69% reduction, p=0.0001 vs placebo; focal impaired awareness, n=86/355, 62% reduction, p<0.0001 vs placebo; focal to bilateral tonic-clonic, n=36/145, 83% reduction, p=0.0045 vs placebo.⁵

^†Post hoc analysis. Groups were: 1 (n=64/397), 2 (n=156/397) or >2 (n=177/397) concomitant ASMs; median baseline seizure frequency/28 days ≤9.5 (n=204/397) or >9.5 (n=193/397); median baseline epilepsy duration ≤23 (n=212/397) or >23 (n=185/397) years.⁶

^‡Adverse reactions reported in clinical studies are listed in the table per system organ class and per frequency. Within each frequency group, undesirable effects are ranked in decreasing order of severity: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to <1/1,000).¹ 

^§Grouped terms: Somnolence: somnolence, fatigue, sedation and hypersomnia; Coordination and gait abnormalities: dizziness, vertigo, balance disorder, ataxia, gait disturbance and abnormal coordination; Hypersensitivity: hypersensitivity, drug hypersensitivity, eyelid oedema; Rash: rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic; Hepatic enzyme increased: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hepatic function abnormal, transaminases increased.¹ 

AE = adverse event; ASM = anti-seizure medication; DRESS = drug reaction with eosinophilia and systemic symptoms; HCP = healthcare professional; MedDRA = Medical Dictionary for Regulatory Activities; mITT-M = modified intention-to-treat maintenance phase; NICE = National Institute for Health and Care Excellence; SMC = Scottish Medicines Consortium; SmPC = Summary of Product Characteristics; SOC = standard of care.

© NICE 2021 Cenobamate for treating focal onset seizures in epilepsy. Technology appraisal guidance TA753. Available from https://www.nice.org.uk/guidance/ta753.
Resource impact statement. Available from https://www.nice.org.uk/guidance/ta753/resources/resource-impact-statement-pdf-14123088042181. All rights reserved. Subject to Notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication.

© SMC 2022 Advice available from https://www.scottishmedicines.org.uk/medicines-advice/cenobamate-ontozry-full-smc2408. All rights reserved. Subject to Notice of rights. SMC advice is prepared for the National Health Service in Scotland. SMC accepts no responsibility for the use of its content in this product/publication.

UK14540P | November 2022