Abstracts

Rationale: Cenobamate (CNB) has a proposed dual mechanism of action including both preferential blockade of persistent sodium currents and positive allosteric modulation of the GABA-A receptor, and is currently FDA-approved for focal-onset seizures in adults. It is currently unknown if CNB may be an effective drug for generalized epilepsies. We investigate the safety and efficacy of CNB in drug resistant patients with genetic generalized epilepsies (GGE) or combined generalized and focal epilepsies (CGFE) which includes developmental and epileptic encephalopathies (DEEs). We also wanted to investigate whether sodium channel blocking property of CNB made seizures worse in CGFE or GGE.

Methods: We performed a retrospective analysis of adult and pediatric patients with generalized epilepsy who were prescribed CNB as identified through Mayo Data Explorer at all Mayo Clinic sites. Patients were divided into 2 cohorts: GGE, including idiopathic generalized epilepsy (IGE), in cohort 1 and CGFE in cohort 2. Demographic information, CNB dosing and duration, seizure responder rates (≥50% reduction), seizure freedom rates, and adverse event data was collected. Patients with < 3 months of follow up on CNB were excluded.  For cohort 2, the diagnosis of CGFE was made if patients had both focal or generalized seizures and interictal EEGs showing both focal and generalized spike wave discharges. In cohort 2, 4 patients had a diagnosis of Lennox-Gastaut syndrome (LGS) and 1 had Dravet syndrome.

Results: In cohort 1, all 3 patients with frequent generalized tonic-clonic seizures (GTCs) had a greater than 50% reduction.  In cohort 2, reduction in both generalized and focal onset seizures was noted and is presented for individual patients. In both cohorts there was a modest effect on other generalized seizures such as absence, myoclonic and tonic seizures. Combining all seizure types there was a 51% mean reduction in seizure frequency and a 76.9% responder rate. No worsening of generalized seizures was seen in any patient . Other important outcomes including improved alertness, decreased seizure severity, reduction or tapering off other ASMs were also noted in both cohorts. Overall, 77% patients experienced adverse events, most of which were managed by slower titration, CNB dose reduction or reducing or tapering off other ASMs.

Conclusions: In our retrospective case series, CNB appears to be an effective ASM for patients with drug resistant GGE and CGFE. Importantly, there was no worsening in generalized seizures despite sodium current blockade mechanism of CNB. Adverse effects may be a limiting factor in some patients. The ongoing CNB trial assessing effectiveness for primary GTCs will provide important data, and additional trials evaluating the response of other generalized seizure types, as well as the use of CNB for DEEs should be considered.

Funding: None