Rationale: Antiseizure medications (ASMs) vary in their spectrum of activity. Appropriate ASM selection depends upon accurate determination of seizure type, which can be difficult and cause delay of epilepsy diagnosis
. Broad-spectrum ASMs treat both focal and generalized seizures, making them valuable treatment options. Cenobamate is an ASM approved for the treatment of focal seizures in adults.
In clinical trials, adjunctive cenobamate demonstrated efficacy in several focal seizure types, including focal to bilateral tonic-clonic (FBTC) seizures. Here we present evidence supporting cenobamate’s potential as a broad-spectrum ASM.
Methods: Cenobamate’s broad-spectrum potential was assessed using preclinical evidence, clinical experience, and real-world evidence.
Results: In preclinical studies, cenobamate showed efficacy or signals of efficacy in rodent models of partial-onset (focal) seizures, including the 6 Hz psychomotor-induced seizure test (median effective dose [ED
50]: 11-18 mg/kg IP) and amygdala kindling test (minimum effective dose: 7 mg/kg IP). Cenobamate was also effective in generalized seizure rodent models, including the maximal electroshock seizure (MES) test (ED
50: 3-10 mg/kg IP; 0.4-3 mg/kg PO) for convulsive seizures and subcutaneous pentylenetetrazol test (SC PTZ; ED
50: 4-29 mg/kg IP; 7-20 mg/kg PO) for nonconvulsive seizures (Melnick 2023).
The cenobamate exposures that demonstrated anticonvulsant effects in rodent models were generally consistent with adult human exposures at ≤200 mg/d. In addition, single cenobamate doses of 100, 250, or 400 mg suppressed the photoparoxysmal response (PPR) in patients with a history of generalized epilepsy in a dose-responsive manner (Kasteleijn-Nolst Trenite 2019).
In two randomized controlled trials, adjunctive cenobamate reduced the median 28-day frequency of FBTC seizures by 77% (vs 33% placebo) during double-blind treatment (Chung 2020, 200 mg/d) and by 51%-92% (vs 33% placebo) during maintenance phase treatment (Krauss 2020, 100-400 mg/d). Case reports suggest cenobamate’s effectiveness in patients with difficult-to-treat seizures, including 4 patients with genetic generalized epilepsy (including 2 patients with idiopathic generalized epilepsy) and 9 patients with combined generalized and focal epilepsies (including developmental and epileptic encephalopathies) (Agashe 2023). Among all 13 patients, the mean reduction of all seizure types was 58%, and the ≥50% responder rate was 70% (SD, ±34.16; median, 50%). Of note, no worsening of generalized seizures has been reported.
Conclusions: The observed potency of cenobamate associated with efficacy in rodent models of generalized seizures is the same magnitude as the potency in rodent models of focal seizures. Cenobamate demonstrated efficacy in preventing the PPR, a type of generalized seizure, in patients. Clinical trial and real-world data also suggest efficacy for generalized tonic-clonic seizures, supporting the broad-spectrum potential for cenobamate. An ongoing phase 3 randomized placebo-controlled trial assessing the effect of cenobamate on primary generalized tonic-clonic seizures in patients ≥12 years of age will evaluate this hypothesis.
Funding: Funded by SK Life Science, Inc.