Abstracts

Rationale: Cenobamate is an antiseizure medication (ASM) approved in the United States, Canada, and Europe for the treatment of focal seizures in adults. Randomized, double-blind studies in patients with uncontrolled focal epilepsy demonstrated the efficacy of cenobamate at various doses (100-400 mg/d). Cenobamate has also demonstrated long-term rates of ≥12-month seizure freedom (SF). A previous post-hoc efficacy analysis of a subset of patients from the large, open-label, phase 3 safety study showed that dose adjustments of concomitant ASMs helped improve retention on cenobamate. Here we examined the various initial doses of cenobamate that were associated with SF in the phase 3 open-label efficacy subset.

Methods: Patients 18-70 years old with uncontrolled focal seizures taking stable doses of 1-3 ASMs were administered increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/d) at 2-week intervals to a target dose of 200 mg/d. Further increases up to 400 mg/d by 50-mg/d increments every other week were allowed during a maintenance phase. Adjustments to concomitant ASMs were allowed. Focal seizure data were available for 240 patients from 10 eligible US study sites. Among patients who achieved SF (ie, 100% seizure reduction) for ≥12 months at the last clinic visit, the initial doses of cenobamate at the start of their seizure-free interval were examined.

Results: Among the 240 patients in the post-hoc efficacy subset, 62 (25.8%) had SF for ≥12 months at their last study visit. Of these 62 patients (median SF duration 25 months [range: 11.6-40.1 months]), 56.5% (35/62) started their seizure-free interval at cenobamate doses of 12.5 to 200 mg/d (Figure 1). The breakdown of cenobamate doses that patients were on at the start of their ≥12 seizure-free interval were 12.5 (n=10), 25 (n=2), 50 (n=3), 100 (n=4), 150 (n=8), 200 (n=8), 250 (n=4), 300 (n=6), 350 (n=5), and 400 (n=12) mg/d. Among the 42 patients who achieved SF for ≥12 months at the last study visit and had < 3 seizures per 28 days at baseline, 61.9% (26/42) started their seizure-free interval on cenobamate doses of 12.5 to 200 mg/d. Among the 20 patients who achieved SF ≥12 months at the last study visit and had ≥3 seizures per 28 days at baseline, 45.0% (9/20) started their seizure-free interval on cenobamate doses of 12.5 to 200 mg/d.

Conclusions: Among the efficacy subset of patients in the open-label phase 3 study who achieved long-term SF for ≥12 months, the initial seizure-free interval occurred at a wide range of cenobamate doses, with some patients requiring higher doses. These data highlight the potential for flexible and individualized dosing with cenobamate, which along with adjustment of concomitant ASMs to improve tolerability, may help more patients achieve optimal seizure reduction. Further research would help determine if the wide range of dosing with cenobamate provides an advantage in achieving seizure reduction, particularly SF, over ASMs with a limited dosing range.

Funding: Funded by SK Life Science, Inc.