Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open‐label safety study

Sperling, Michael R.; Klein, Pavel; Aboumatar, Sami; Gelfand, Michael; Halford, Jonathan J.; Krauss, Gregory L.; Rosenfeld, William E.; Vossler, David G.; Wechsler, Robert; Borchert, Leona D.; Kamin, Marc

doi:10.1111/epi.16525

Cited by 128 publications

(233 citation statements)

References 25 publications

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“…Remarkably, the interim report from the ongoing phase III safety study provided dosing guidance for the real-world management of patients taking cenobamate and concomitant phenytoin or phenobarbital, who instead were excluded from the RCTs. In this study, which allows dose adjustment of concomitant ASMs based on the patient's clinical condition and plasma levels, around 45 and 30% of patients taking phenytoin and phenobarbital had their doses decreased [35]. At the end of the titration, the mean plasma levels of phenytoin and phenobarbital were generally comparable to those obtained before the start of cenobamate, suggesting that periodic dose reductions of 25-33% in response to AEs can be effective to maintain stable plasma levels [35].…”

Section: Pharmacological Interactionsmentioning

confidence: 74%

“…Three of these events, including the case of DRESS, occurred early during treatment, at the start of the drug or during the titration schedule. During early clinical development, three confirmed cases of DRESS were also identified among the first 953 participants exposed to cenobamate, including one fatality [31]. Cutaneous, idiosyncratic AEs have been reported with ASMs.…”

Section: Summary Of Main Resultsmentioning

confidence: 95%

“…In this study, which allows dose adjustment of concomitant ASMs based on the patient's clinical condition and plasma levels, around 45 and 30% of patients taking phenytoin and phenobarbital had their doses decreased [35]. At the end of the titration, the mean plasma levels of phenytoin and phenobarbital were generally comparable to those obtained before the start of cenobamate, suggesting that periodic dose reductions of 25-33% in response to AEs can be effective to maintain stable plasma levels [35]. In the same way, a reduction in dosage of clobazam should be considered, as clinically appropriate, to counteract the increase in plasma concentrations of desmethylclobazam, the active metabolite of clobazam, that occurs when cenobamate is concomitantly prescribed [10].…”

Section: Pharmacological Interactionsmentioning

confidence: 99%

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Adjunctive Cenobamate for Focal-Onset Seizures in Adults: A Systematic Review and Meta-Analysis

et al. 2020

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Background Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. This drug can enhance the inactivated state of voltage-gated sodium channels, preferentially inhibiting the persistent component of the sodium channel current, and acts as a positive allosteric modulator of GABA A receptors, binding at a non-benzodiazepine site. Objective We assessed the efficacy and safety of adjunctive cenobamate for the treatment of focal-onset seizures in adult patients with epilepsy using meta-analytical techniques. Methods We systematically searched (May, week 4, 2020) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry (http://www.clini caltr ials.gov). There were no date limitations or language restrictions. Randomized, placebo-controlled, single or doubleblinded, add-on trials of cenobamate in adult patients with uncontrolled focal-onset seizures were identified. Main outcomes included the proportion of patients with ≥ 50 and 100% reduction in seizure frequency during the maintenance treatment period compared with baseline and the incidence of treatment withdrawal and adverse events (AEs). Risk ratio (RR) with 95% confidence interval (CI) was estimated for each outcome. Results Two trials were included, overall enrolling 659 patients (442 for the add-on cenobamate group and 217 for the add-on placebo group). Seizure frequency reduction by at least 50% occurred during the maintenance phase in 50.1% of the patients randomized to cenobamate and 23.5% of the placebo-treated participants (RR 2.18, 95% CI 1.67-2.85; p < 0.001). The pooled estimated RR to achieve seizure freedom for the cenobamate group in comparison with placebo was 3.71 (95% CI 1.93-7.14; p < 0.001). Withdrawal from randomized treatment occurred in 16.7 and 11.1% of participants receiving cenobamate and placebo, respectively (RR 1.34, 95% CI 0.85-2.09; p = 0.205). Treatment was discontinued due to AEs in 12.2 and 4.1% of the patients in the active and control arms (RR 2.27, 95% CI 1.08-4.79; p = 0.031). AEs were reported in 76.9 and 66.8% of the patients during treatment with cenobamate and placebo (RR 1.14, 95% CI 1.02-1.26; p = 0.021). The cenobamate-associated AEs included somnolence, dizziness, fatigue, balance disorder, and diplopia. Conclusions Adjunctive cenobamate in adult patients with uncontrolled focal-onset seizures is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

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Section: Pharmacological Interactionsmentioning

confidence: 74%

Section: Summary Of Main Resultsmentioning

confidence: 95%

Section: Pharmacological Interactionsmentioning

confidence: 99%

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Adjunctive Cenobamate for Focal-Onset Seizures in Adults: A Systematic Review and Meta-Analysis

et al. 2020

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“…It has been demonstrated to reduce focal seizures in two phase 2 clinical studies (NCT01397968 and NCT01866111) compared to placebo [7,8]. In addition, an interim analysis of an ongoing open-label phase 3 safety study (NCT02535091) demonstrated safety and tolerability of cenobamate over a duration of approximately 6.5 months [9]. Cenobamate is prepared as an oral film-coated tablet that is soluble in water (1.7 mg/mL).…”

Section: Key Pointsmentioning

confidence: 99%

An Ex Vivo Evaluation of Cenobamate Administered via Enteral Tubes

et al. 2020

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Background Cenobamate is a new, Food and Drug Administration (FDA)-approved oral antiepileptic drug for treatment of focal seizures in adults. This study examined recovery of cenobamate from suspensions administered through ex vivo enteral feeding tubes. Methods Suspensions containing 100 and 200 mg of cenobamate were prepared (five duplicates for each dose), passed through five vertically standing tubes, and collected into flasks. The flasks containing the suspensions were rinsed with deionized water, and this content was also injected into the tubes and collected in the flasks. Acetonitrile, isopropyl alcohol, and trifluoroacetic acid were added to the flasks, followed by deionized water to a concentration of 500 (100-mg cenobamate) and 400 (200-mg cenobamate) µg/mL. A 3-mL aliquot from each suspension was placed into a 10-mL flask, diluted to volume, and mixed, resulting in final concentrations of 150 and 120 µg/mL, respectively. All suspensions were analyzed by high-performance liquid chromatography (LC). The % LC recovery of cenobamate was calculated for each suspension, and mean % LC for duplicates. Results The % LC recovery of cenobamate from the 100-mg suspensions ranged from 96.2 to 99.1%, with mean % LC recovery between 96.3 and 98.3%. The % LC recovery of cenobamate from the 200-mg suspensions ranged from 97.1 to 102.6%, with mean % LC recovery between 98.5 and 101.7%. Conclusion The mean % LC recovery of cenobamate was within the predetermined acceptable range of 90.0-110.0%, suggesting no adhesion or adsorption of cenobamate to enteral feeding tubes. Delivery of cenobamate suspension via enteral feeding tubes may be a viable route of administration for patients who cannot swallow tablets.

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“…Relatively recently, two novel antiepileptic drugs (AEDs, cenobamate and perampanel, have been licensed and approved as add-on drugs to clinical practice by FDA in USA and EMA in the EU [1,2]. At present, physicians can prescribe for epileptic patients approx.…”

Section: Introductionmentioning

confidence: 99%

Three-drug combination of lacosamide, phenobarbital and valproate exerts additive interaction in the tonic-clonic seizure model in mice

Kondrat-Wróbel

Marzęda

Bojar

et al. 2020

J Pre Clin Clin Res.

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Introduction. Triple-therapy with antiepileptic drugs (AEDs) is usually prescribed for epilepsy patients, whose seizures are not fully controlled with standard medications. Although 25 various AEDs are currently licensed for treating epilepsy, no algorithms allowing for the proper combination of AEDs are available. Objective. The aim of the study is to isobolographically assess the type of interaction among three AEDs (lacosamide [LCM], phenobarbital [PB] and valproate [VPA]), in the model of tonic-clonic seizures in mice. Materials and Method. The electrically-evoked (25 mA, 500 V, 50 Hz, 0.2 s of stimulus duration) tonic-clonic seizures in male albino Swiss mice allowed determination of the anticonvulsant action of the three-drug mixture of LCM, PB and VPA combined in a dose ratio of 1:1:1 by means of type I isobolographic analysis of interaction. Results. The experimentally-determined ED50 exp value for the three-drug mixture was 112.04 mg/kg and did not differ from the theoretically calculated ED50 add value, which was 112.36 mg/kg. Lack of statistical significance confirmed that the mixture of LCM, PB and VPA in a dose-ratio of 1:1:1 exerted additive interaction in the mouse tonic-clonic seizure model. Conclusions. Although the three-drug combination of LCM, PB and VPA produced additive interaction in the mouse tonic-clonic seizure model, the three-drug combination could be recommended for epilepsy patients whose seizures are refractory to the standard medication.

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Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open‐label safety study

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 128 publications

References 25 publications

Adjunctive Cenobamate for Focal-Onset Seizures in Adults: A Systematic Review and Meta-Analysis

Adjunctive Cenobamate for Focal-Onset Seizures in Adults: A Systematic Review and Meta-Analysis

An Ex Vivo Evaluation of Cenobamate Administered via Enteral Tubes

Three-drug combination of lacosamide, phenobarbital and valproate exerts additive interaction in the tonic-clonic seizure model in mice

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