Rationale:
Cenobamate is an antiseizure medication (ASM) approved in the US for treatment of focal (partial-onset) seizures in adults. In two phase 2, randomized, double-blind, placebo-controlled studies, 21% of patients (Study C017) and 28% of patients (Study C013) with uncontrolled focal seizures treated with adjunctive cenobamate achieved 100% seizure reduction (seizure freedom) during the maintenance phase. A global phase 3, long-term, open-label study (C021) assessed the safety of cenobamate. This post-hoc analysis assessed whether baseline seizure frequency impacted the mean cenobamate dose required to achieve seizure freedom, using data from 10 eligible US study sites.
Method:
Adults 18-70 years old with uncontrolled focal seizures taking stables doses of 1-3 ASMs were initiated on adjunctive cenobamate at a dose of 12.5 mg/day for 2 weeks, with increasing daily doses (25, 50, 100, 150, and 200 mg) at 2-week intervals. Further increases to a maximum of 400 mg/day (using biweekly increments of 50 mg/day) were permitted during a dose-optimization/maintenance phase. Patient visits occurred every 2 weeks for 16 weeks and then every 1-3 months. A protocol amendment permitted for the post-hoc collection of seizure data.
Results:
Overall, 249 patients (N=1347 enrolled) who received at least one dose of cenobamate from 10 US sites were evaluable for the analysis (141 males [mean age 39.5 years] and 108 females [mean age 45.4 years]). The retention rate was 73.5% (183/249 continuing to receive cenobamate) as of the last reported 3-month clinic visit. In patients still receiving cenobamate, the mean duration of time on-study was 33.9 months, representing 517 patient-years of exposure, and the mean cenobamate dose was 286.1 mg/day. Sixty-two of 183 (33.9%) patients were seizure-free for ≥12 months at the last clinic visit, with a mean seizure-free duration of 23.6 months. The mean cenobamate dose in these patients was 251.6 mg/day. Of the 62 seizure-free patients, 35 (56.5%) experienced <2 seizures per 28 days and 27 (43.5%) experienced >2 seizures per 28 days at baseline. The mean cenobamate dose in these patients was 238.6 and 268.5 mg/day, respectively. Decreases in seizure frequency during dose titration occurred with doses ≥25 mg/day in the group with <2 seizures per 28 days and with doses ≥12.5 mg/day in the group with >2 seizures per 28 days at baseline (Figure). The most common treatment-emergent adverse events were dizziness, diplopia, drowsiness, and somnolence. No cases of DRESS were reported.
Conclusion:
As of their last visit, 33.9 % of patients treated with cenobamate had 100% seizure reduction for ≥12 months. The percent of seizure-free patients and their mean dose of cenobamate did not vary significantly when stratified by baseline seizure frequency. However, the less intractable group with <2 seizures per 28 days at baseline required approximately 30 mg less cenobamate for their daily dosage. Both groups had decreases in seizure frequency during cenobamate dose titration.
Funding:
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Funding:
: SK Life Science, Inc.
FIGURES
Figure 1