Cenobamate cuts SUDEP risk

A study presented at EAN 2025 demonstrates a reduction in the risk of sudden unexpected death in epilepsy (SUDEP) following treatment with the antiseizure medication (ASM) cenobamate among Spanish individuals in the phase III C021 study. The reductions were based on SUDEP-3 and SUDEP-7 risk scores.

C021 is an open-label phase III study evaluating the safety and tolerability of adjunctive cenobamate in adults who were on 1–3 ASMs for the management of uncontrolled focal seizures. This retrospective analysis of the Spanish cohort of C021 (n=127) collected efficacy and safety data before and after cenobamate administration. In this analysis, the mean age of participants was 39.7 years, and 56.7 percent were women. The median baseline seizure frequency per 28-day cycle was six.

The baseline SUDEP-3 and SUDEP-7 risk scores were compared against the risk scores reported at years 1 and 2. Each point gained corresponds to an increased odds of SUDEP (by 180 percent for SUDEP-3 and 40 percent for SUDEP-7).

The risk factors evaluated in the SUDEP-3 inventory are generalized tonic-clonic seizure (GTCS) frequency >3 in the last year, seizure of any type >0 in the last year, and intellectual disability. For SUDEP-7, the risk factors are GTCS frequency >3 and >0 in the last year, seizure of any type >50 and >0 in the last year, use of >2 ASMs, duration of epilepsy >30 years, and intellectual disability (IQ <70).

At baseline, all patients had risk scores of at least 2 out of 4 (76 percent had a score of 2; 24 percent had a score of 3) for SUDEP-3 and 1 out of 10 (52 percent had scores of 1–3; 48 percent had scores of 4–8) for SUDEP-7. [EAN 2025, abstract A-25-14044]

Two years from baseline

After 2 years of cenobamate treatment, more participants had lower SUDEP-3 and SUDEP-7 risk scores, the researchers noted.

For the SUDEP-3 risk score, three-quarters of participants had a score of 2, and only 8 percent had a score of 3. Notably, 17 percent had a score of 0 vs none at baseline. Specifically, 31 percent of patients had a ≥1-point decrease in risk score (14 percent had a 1-point reduction, 11 percent had a 2-point reduction, 6 percent had a 3-point reduction).

Sixty-nine percent of participants had a stable SUDEP risk. For each point decrease in the SUDEP-3 risk score, the odds of SUDEP drop by 64 percent, the researchers explained.

For SUDEP-7, 18 percent of participants had a score of 1 as opposed to only 2 percent at baseline. Forty-nine percent had a ≥1-point drop in risk score, with most (39 percent) having a decrease of 1–2 points; the remaining 10 percent had a reduction of 3–4 points. Forty-four percent had a stable SUDEP risk, and each point reduction corresponded to a decrease in the odds of SUDEP by 29 percent.

Of note, 7.5 percent of patients had an increased risk of SUDEP. The researchers attributed this primarily to longer disease duration (<30 years).

Sustained seizure freedom achieved

In patients with epilepsy, SUDEP accounts for 2–17 percent of deaths. The estimated cumulative lifetime risk of SUDEP is 35 percent. [Neurol Int 2022;14:600-613]

“[In this retrospective analysis,] sustained seizure freedom, including seizure freedom from focal to bilateral TCS, was achieved with cenobamate, resulting in a statistically significant reduction in SUDEP risk as measured by the two validated SUDEP risk assessment tools,” said the researchers.

The potential to reduce SUDEP risk should be considered when initiating and/or changing treatment in individuals with uncontrolled focal seizures, they concluded.

Cenobamate is approved in Europe as an adjunctive therapeutic agent for adults who have inadequately controlled focal seizures despite a history of treatment with ≥2 ASMs. [Front Pharmacol 2023;14:1239152]