Cenobamate Continues to Show Durable Efficacy in Reducing Seizure Frequency

William E. Rosenfeld, MD

Two newly published post-hoc analyses from the phase 3 open-label safety study, C021 (NCT02535091), showed that long-term treatment with cenobamate (Xcopri; SK Life Science) provided safe and effective reduction of seizure frequency, and was associated with concomitant antiseizure medication (ASM) dose reductions.^1-3

Study C021 was a multicenter study assessing the safety of cenobamate as adjunctive therapy in 1340 adults, aged 18 to 70 years, with uncontrolled focal seizures taking 1-3 ASMs. Cenobamate, an FDA-approved medication for partial-onset seizures, was initiated at 12.5 mg per day and increased at 2-week intervals to 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg per day for at least 6 months.

"The results of these 2 new post-hoc analyses provide evidence of the durable efficacy of Xcopri, as many patients sustained 90% and 100% reductions of their seizures over the course of the entire maintenance period, lasting up to 40.2 months," lead investigator William E. Rosenfeld, MD, neurologist, Comprehensive Epilepsy Care Center for Children and Adults, in St Louis, Missouri, said in a statement.¹

The first analysis included 255 patients, 240 of whom had focal aware motor, focal impaired awareness, or focal to bilateral tonic-clonic seizure data available while on treatment. In total, 74% (n = 177) of patients remained on the study drug throughout the entire analysis period (media exposure, 2.7 years). During the entire maintenance treatment duration, 13.1% (n = 28) of those achieved 100% seizure reduction while 40.2% (n = 86) achieved at least a 90% reduction. Additionally, 36.3% (n = 87) of patients had 100% reduction for at least 12 consecutive months during the study.²

For the total treatment duration, 71.7% (n = 172) of patients experienced at least 50% response rate to treatment. During titration, these rates were 48.1% during weeks 1-4 (12.5-25 mg/day cenobamate) and 61.7% during weeks 5-8 (50-100 mg/day cenobamate). Common treatment-emergent adverse events (AEs), which included fatigue (34.6%), dizziness (32.1%), and somnolence (29.6%) were consistent with those in patients from the primary study.

"I am encouraged to see the high retention rates associated with Xcopri. Many patients continued on Xcopri and remained seizure free, while also reducing or discontinuing one or more concomitant ASMs," Rosenfeld added.¹ "These analyses may provide clinicians with real-world insight on managing their patients’ seizures, minimizing drug burden, while potentially reducing the side effects of concomitant ASMs associated with epilepsy treatment."

The second post-hoc analysis reported on how patients adjusted baseline ASMs while on cenobamate. The most commonly reported baseline concomitant ASMs were lacosamide (Vimpat; UCB), levetiracetam (Keppra; UCB), lamotrigine (Lamitcal; GSK), zonisamide (Zonegran; Eisai), and clobazam (Onfi; Lundbeck). For these ASMs, mean dose reductions and percentage change in dose from baseline to last dose were greater in patients continuing cenobamate vs those who discontinued.³

The greater retention rate for these ASMs—ranging from 71.9% to 78.9% for patients who continued cenobamate and from 21.1% to 28.1% for those who discontinued the study drug—were observed for those who had larger concomitant ASM dose reductions. The percent dose change ranged from –65.8% to –23.4% for those continuing the study drug compared with –7.8% to –25.0% for those who discontinued. The findings suggest that “the cenobamate efficacy was not impaired by decreasing the dose of concomitant ASMs, and that cenobamate tolerability may have improved with greater concomitant ASM dose reductions,” according to investigators.

Among patients continuing cenobamate, 24.6% (97 of 395) completely discontinued 1 or more of their concomitant ASMs. Lacosamide, levetiracetam, and perampanel (Fycompa; Eisai) were the ASMs discontinued in the greatest number of patients overall, with 18, 13, and 11 patients, respectively, discontinuing these concomitant ASMs completely.

Percentages of responders by concomitant ASM in the maintenance population (n = 214) ranged from about 75% of patients with at least 50% response to about 13% for 100% response. For those who continued the study drug at cut-off with concomitant ASM, ~81% were at least 50% responders and about 12% achieved 100% reduction in seizures for the entire maintenance phase. Investigators wrote that "the duration of which was much longer than what is typically reported in open-label long-term extension studies that provide 100% seizure reduction rates."³

Rosenfeld sat down with NeurologyLive earlier this year to discuss phase 3 results of cenobamate presented at the 2020 American Epilepsy Society Annual Meeting. He provided insight on the sizable decrease in concomitant ASM use that was observed, as well as the clinical value cenobamate holds.

REFERENCES

1. Epilepsia publishes 2 post-hoc analyses from long-term study of Xcopri (cenobamate tablets) CV. News release. SK Life Science. October 12, 2021. Accessed October 20, 2021. https://www.sklifescienceinc.com/pdf/Epilepsia_Publishes_Two_Post-hoc_Analyses_From_Long-Term_Study_Of_XCOPRI%C2%AE_%28cenobamate%20tablets%29_CV%20%281%29.pdf

2. Sperling M, Abou-Khalil B, Aboumatar S, et al. Efficacy of cenobmate for uncontrolled focal seizures: post-hoc analysis of a phase 3, multicenter, open-label study. Epilepsia. Published online October 11, 2021. doi:10.1111/epi17091

3. Rosenfeld WE, Abou-Khalil B, Aboumatar S, et al. Post-hoc analysis of a phase 3, multicenter, open-label study of cenobamate for treatment of uncontrolled focal seizures: effects of dose adjustments of concomitant antiseizure medications. Epilepsia. Published October 11, 2021. doi:10.1111/epi.17092