Cenobamate as add-on treatment for SCN8A development and epileptic encephalopathy

ObjectivesDevelopmental and epileptic encephalopathies (DEEs) caused by pathogenic variants in SCN8A are associated with difficult-to-treat and early-onset seizures, developmental delay/intellectual disability, impaired quality of life, and increased risk of early mortality. Commonly used antiseizure medications (ASMs) for SCN8A-related disorders, caused by gain-of-function variants, are sodium channel blockers. The use of such ASMs is often not enough to gain satisfactory seizure control. In this retrospective study, the effect of cenobamate was assessed in patients with SCN8A-DEE. MethodsAcross multiple centers and through a collaboration with the patient advocacy organization International SCN8A Alliance, patients with SCN8A-DEE treated with cenobamate for [≥]3 months were identified. Data were obtained once from patients caregivers or treating physicians through a RedCap survey. The functional effects of the included patients SCN8A variants were determined by functional tests published in the literature or functionally classified by prediction tools. ResultsTwelve patients (2-25 years, 8 females) with presumed gain-of-function SCN8A variants were treated with cenobamate for a mean period of 8.6 months (range 3-27 months). Countable motor seizures were reduced in 12/12 (100%) patients. Seven experienced a seizure reduction above 75% of which two patients achieved seizure freedom. A 25-50% and 50-75% decrease was observed in three and two patients, respectively. An increase in seizure-free days/patient was also reported. Rescue medication was decreased in 83% of patients, and non-seizure-related improvements (increased alertness, better sleep, improved muscle tone) were observed in 58%. Adverse effects were reported by 33%; half resolved spontaneously or by the reduction of concomitant ASMs. SignificanceOur data suggest, that cenobamate is a promising and safe treatment for SCN8A- DEE, even during early infancy. As a possible precision approach to treatment, cenobamate effectively reduced seizure burden and ameliorated non-seizure-related symptoms. Similar results may be achieved in cohorts of patients with gain-of-function variants encoding other sodium channels. Key pointsO_LIPatients with DEE caused by pathogenic GOF variants in SCN8A are commonly treated with sodium channel blockers, often without satisfying seizure control. C_LIO_LIAdjunctive cenobamate improved seizure frequency in 12/12 patients (2-25 years, 8 females) with SCN8A-DEE of which two achieved seizure freedom. C_LIO_LIAn increase in seizure-free days/patient, non-seizure-related improvements (e.g. increased alertness), and a decrease in rescue medication was also observed. C_LIO_LICenobamate is a promising and safe treatment for SCN8A-DEE, even during early infancy. C_LIO_LISimilar results may be achieved in patients with gain-of-function variants encoding other sodium channels. C_LI