Objective:

To assess all-cause mortality and sudden unexpected death in epilepsy (SUDEP) during the cenobamate clinical trial program.

Background:

The all-cause mortality rate in people with epilepsy is higher than in the general population for various reasons, including SUDEP. In a pooled analysis of 4 antiseizure medication (ASM) development programs involving 9144 adults and children with 13,617 person-years, all-cause mortality and SUDEP rates were 9.1 and 3.8, respectively, per 1000 person-years.

Design/Methods:

We analyzed deaths among 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 2.8-11 seizures/28 days; median epilepsy duration ranged from 20-24 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. Deaths were evaluated by 2 epileptologists. All-cause mortality and SUDEP rates were expressed per 1000 person-years.

Results:

2131 patients (n=2017 focal epilepsy; n=114 idiopathic generalized epilepsy) were exposed to cenobamate for 5693 person-years; ~60% of patients with focal seizures and all patients in the PGTC study had tonic-clonic seizures. Twenty-three deaths occurred (all in patients with focal epilepsy), for an all-cause mortality rate of 4 per 1000 person-years. Five cases of definite or probable SUDEP were identified for a rate of 0.88 per 1000 person-years. Of the 23 deaths, 21 patients (91%) had FBTC, and 4 of the 5 SUDEP patients had FBTC seizures. Duration of cenobamate exposure for patients with SUDEP ranged from 130-620 days.

Conclusions:

The all-cause mortality and SUDEP rates among patients with uncontrolled seizures enrolled in the cenobamate development program compare favorably to previously reported rates in other ASM development programs.