Abstracts

Rationale: The all-cause mortality rate in people with epilepsy (PWE) is higher than in the general population for various reasons, including sudden unexpected death in epilepsy (SUDEP). Mortality rates for PWE evaluated from antiseizure medication (ASM) clinical trial databases provide accurate data for patients with uncontrolled seizures. In a pooled analysis of four ASM development programs involving 9,144 adults and children with 13,617 person-years, all-cause mortality and SUDEP rates were 9.1 and 3.8, respectively, per 1,000 person-years. In community-based populations, the risk of SUDEP ranges from 0.35 to 2.3 per 1,000 person-years. Higher SUDEP rates of up to 9.3 deaths per 1,000 person-years are reported in drug-resistant epilepsy surgery candidates. We assessed all-cause mortality and SUDEP during the cenobamate clinical trial program.

Methods: We analyzed deaths among all adults with uncontrolled focal (focal to bilateral tonic-clonic [FBTC], focal impaired awareness, focal aware) or primary generalized tonic-clonic (PGTC) seizures who received ≥ 1 dose of adjunctive cenobamate in completed and ongoing phase 2 and 3 clinical studies. In patients with focal seizures from completed studies, median baseline seizure frequencies ranged from 2.8 to 11 seizures per 28 days and median epilepsy duration ranged from 20 to 24 years. Total person-years included all days a patient received cenobamate during completed studies or up to a June 1, 2022, cutoff for ongoing studies. All deaths were evaluated by two epileptologists. All-cause mortality and SUDEP rates were expressed per 1,000 person-years.

Results: A total of 2,131 patients (n = 2,017 focal epilepsy; n = 114 idiopathic generalized epilepsy) were exposed to cenobamate for 5,693 person-years. Approximately 60% of patients with focal seizures and all patients in the PGTC study had tonic-clonic seizures. A total of 23 deaths occurred (all in patients with focal epilepsy), for an all-cause mortality rate of 4 per 1,000 person-years. Five cases of definite or probable SUDEP were identified for a rate of 0.88 per 1,000 person-years. Of the 23 overall deaths, 21 patients (91%) had FBTC, and 4 of the 5 SUDEP patients had FBTC seizures. Duration of exposure to cenobamate for patients with SUDEP ranged from 130 to 620 days.

Conclusions: The rate of all-cause mortality (4 per 1,000 person-years) and SUDEP (0.88 per 1,000 person-years) among patients with uncontrolled seizures enrolled in the cenobamate development program compares favorably to previously reported rates in other ASM development programs and the rate of SUDEP is similar to reported rates in community-based analyses of patients with epilepsy.

Funding: SK Life Science, Inc.