Reduction in Concomitant Antiseizure Medications Improves Cenobamate Retention Rates

William Rosenfeld, MD

Post hoc analysis from a phase 3 study presented at the American Epilepsy Society (AES) Annual Meeting, December 4–8, 2020, suggest that reducing doses of concomitant antiseizure medications (ASMs) led to fewer patients with focal seizures discontinuing cenobamate (Xcopri; SK Life Science).¹

The data, presented by William Rosenfeld, MD, neurologist, Comprehensive Epilepsy Care Center, showed that patients who continued on cenobamate had greater decreases in mean concomitant ASM use (first vs last dose) compared to those who discontinued.

Rosenfeld and colleagues noted that these dose decreases were mostly due to adverse events (AEs), mainly during titration or early maintenance phases when cenobamate doses were escalated, suggesting tolerability of a combination treatment may have led to cenobamate discontinuation.

Overall, the analysis included 249 patients with uncontrolled focal seizures on stable doses of 1–3 ASMs. In an effort to examine how dose adjustments to concomitant ASMs impacted tolerability and retention of adjunctive cenobamate, researchers gave dose increases of 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg per day at 2-week intervals. Patients were permitted to increase up to 400 mg of cenobamate by 50-mg-per-day increments biweekly if needed. Adjustments to concomitant ASMs were also allowed. Of the 249 patients included in the data, 183 remained on cenobamate (73.5% retention).

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In total, phenytoin, clobazam, and lacosamide were the 3 ASMs that were lowered earlier and resulted in better retention of cenobamate. Phenytoin was lowered due to pharmacokinetic (PK) interactions and to lessen the occurrence of AEs such as somnolence, dizziness, and ataxia, whereas clobazam was decreased due to PK interactions and to lessen somnolence and sleepiness. Lacosamide was decreased because of probable pharmacodynamic interaction and to lessen dizziness and unsteadiness.

Among the cohort of patients who remained on cenobamate, 91 of the 401 (22.7%) concomitant baseline ASM dosesere discontinued completely. Carbamazepine accounted for 28.6% of patients, oxycarbazepine for 25%, lacosamide for 21.5%, eslicarbazepine for 23.1%, clobazam for 22.6%, lamotrigine for 15.4%, and levetiracetam for 14.1%.

Investigators noted that most of the patients had significant reductions in seizure frequency across focal seizure types. When 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.

Notably, 12% of patients saw a temporary increase in seizure numbers, but high retention rates and number of patients remaining seizure-free for prolonged periods indicated the efficacy of cenobamate. Among those who continued cenobamate treatment, 33.9% reported seizure freedom for a mean 23.6 months at last visit.

This is not the first time that effects of cenobamate with other ASMs have been studied. Data from a post-hoc analysis of the YKP3089C017 (C017; NCT01866111) study demonstrated a reduction in seizure frequency with treatment with cenobamate in patients with epilepsy, regardless of their baseline number of antiepileptic drugs (AEDs).

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REFERENCES

1. Rosenfeld W, Aboumatar S, Bhatia P, et al. Dose adjustments to concomitant antiseizure medications: post-hoc analysis of a phase 3, open-label study of cenobamate for the treatment of uncontrolled focal seizures. Presented at AES 2020 Annual Meeting; December 4–8, 2020. Abstract 336.

2. Rosenfeld WE, Nisman A, Cho JW, Ferrari L. Efficacy of adjunctive cenobamate in patients with uncontrolled focal seizures based on number of concomitant antiepileptic drugs, seizure frequency, and epilepsy duration at baseline. Neurology. 2020;94(15 Suppl): 1025.