Abstracts

Rationale:
Epilepsy patients are frequently on multiple concomitant antiseizure medications (ASMs) that can have interactions affecting efficacy/tolerability. Cenobamate is an ASM approved in the US for uncontrolled focal seizures. This post-hoc analysis examined how dose adjustments to concomitant ASMs impacted tolerability and retention in patients from 10 US study sites in an ongoing, global, phase 3 study (N=1347 enrolled) of adjunctive cenobamate.
Method:
Patients with uncontrolled focal seizures on stable doses of 1-3 ASMs were enrolled. Dose increases of cenobamate (12.5, 25, 50, 100, 150, and 200 mg/day) occurred at 2-week intervals. Increases up to 400 mg/day by 50-mg/day increments biweekly were permitted. Adjustments to concomitant ASMs were allowed.
Results:
Data from 249 patients were available; 183 remained on cenobamate (73.5% retention). Baseline concomitant ASMs and patients who continued or discontinued cenobamate by ASM are shown in the Table. For most concomitant ASMs, patients who continued cenobamate had greater decreases in mean concomitant ASM dose (first vs last dose) vs those who discontinued (Table). These dose decreases were mostly due to adverse events, mainly during titration or early maintenance phases when cenobamate doses were escalated, suggesting tolerability of combination treatment may have led to cenobamate discontinuation. Three ASMs were lowered earlier and resulted in better retention: phenytoin (decreased due to pharmacokinetic [PK] interactions and to lessen somnolence/dizziness/ ataxia), clobazam (decreased due to PK interactions and to lessen somnolence/sleepiness), and lacosamide (probable pharmacodynamic interaction; decreases reduced dizziness/unsteadiness). Of patients remaining on cenobamate, 91/401 (22.7%) concomitant baseline ASMs were discontinued completely, including carbamazepine in 28.6% of patients, oxcarbazepine in 25%, lacosamide in 21.5%, eslicarbazepine in 23.1%, clobazam in 22.6%, lamotrigine in 15.4%, and levetiracetam in 14.1%. Timing of concomitant drug dose adjustment and cenobamate dose are shown in the Figure. Of 183 patients remaining on cenobamate, 173 were included in the efficacy analysis. Most had significant reductions in seizure frequency across focal seizure types. Comparing total baseline seizure frequency to last 3-month visit, 85% of patients had ≥50 % reduction, 74% had ≥75% reduction, and 57.2% had 100% reduction in seizures. Temporary increase in seizure numbers at an individual visit occurred in ~12% of patients, but high retention rates and number of patients remaining seizure-free for prolonged periods (33.9% of those who continued cenobamate were seizure-free for a mean 23.6 months at last visit) indicates the efficacy of cenobamate.
Conclusion:
This post-hoc analysis suggests that reducing doses of concomitant ASMs, across a range of drugs with multiple mechanisms of action, led to fewer patients discontinuing cenobamate. Decreasing doses of phenytoin, clobazam, and lacosamide were the earliest clinically performed.
Funding:
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Funding:
: SK Life Science, Inc.