Cenobamate Significantly Improves Seizure Control in Adults With Uncontrolled Focal Seizures

Marc Kamin, MD

Data from 2 phase 3 studies—Study 013 and Study 021— revealed that treatment with cenobamate (Xcopri; SK Life Science) significantly improved seizure control in adults with uncontrolled focal seizures, as well as showed a high rate of sustained retention at 6 months.¹

Results from Study 013 (NCT01397968) published in Neurology, which included 222 patients randomized to cenobamate (n = 113) and placebo (n = 109), showed a 55.6% median seizure reduction for those treated with cenobamate compared with 21.5% in placebo group (P <.0001). Additionally, responder rate, defined as >50% reduction in seizure frequency) was 50.4% for cenobamate and 22.2% for placebo (P <.0001). These data were published by Arvelle Therapeutics, which has the rights to develop and commercialize cenobamate in Europe. ²

Senior researcher Marc Kamin, MD, chief medical officer, SK Life Sciences, and colleagues documented 28.3% of cenobamate-treated and 8.8% of placebo-treated patients were seizure free during the maintenance period, respectively.

Data also showed that 76.3% of cenobamate-treated and 27.8% of placebo-treated groups who had focal aware motor seizures (cenobamate, n = 30; placebo, n = 26) experienced median reduction in 28-day seizure frequency from baseline (P = .0448). Additionally, 77% and 33% of patients with focal to bilateral tonic-clonic seizures (cenobamate, n = 38; placebo, n = 37) experienced median seizure frequency reduction at 28-days from baseline (P = .0117).

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When evaluating the safety profiles, treatment-emergent adverse events (TEAEs) reported in >10% in either group (cenobamate vs placebo) were somnolence (22.1% vs 11.9%), dizziness (22.1% vs 16.5%), headache (12.4% vs 12.8%), nausea (11.5% vs 4.6%), and fatigue (10.6% vs 6.4%).

In addition to Study 013, published interim results from phase 3, Study 021 of 1339 adults with uncontrolled focal seizures demonstrated that 83% of patients treated with cenobamate retained the drug beyond 6 months. Additionally, no cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome were reported.³

“This trial represents an important advancement in the development of cenobamate for adult patients with focal onset seizures, and its publication in Neurology adds to the body of evidence for the efficacy and safety of cenobamate,” Ilise Lombardo, MD, co-founder and chief medical officer, Arvelle, said in a statement of Study 013 data. “The study results suggest that cenobamate may offer a potential treatment option for patients who continue to have seizures despite the use of available treatments.”

Study 021 is an open-label study that assesses the safety of a cenobamate in adults, 18 to 70 years old with uncontrolled focal onset seizures taking at least 1 antiseizure medication (ASM). The therapy was initiated at 12.5 mg/day and increased at 2-week intervals to 25, 50, 100, and 200 mg/day. During titration, patients taking phenytoin or phenobarbital could not have their cenobamate titration rate or other concomitant ASMs adjusted; phenytoin and phenobarbital doses could be decreased by 25% to 33%.

The common treatment-emergent adverse events (TEAEs) were somnolence (28.1%), dizziness (23.6%), and fatigue (16.6%). Serious TEAEs occurred in 108 patients (8.1%), most commonly seizure (n = 14), epilepsy (n = 5), and pneumonia, fall, and dizziness (n = 4 each).

In the phenytoin/phenobarbital groups, 43.4% (36/114) and 29.7% (11/51) of patients, respectively, had their doses decreased. Mean plasma phenytoin/phenobarbital levels were generable comparable to baseline at the end of titration.

“The high retention rates of 83% seen in this interim report means that more people may potentially benefit from cenobamate.” Lombardo said. “Retention rates provide an indication of overall clinical outcome, serving as a combined proxy measure for efficacy and safety over time. It´s also reassuring to see that no cases of DRESS syndrome occurred, suggesting that initiating cenobamate at a low dose and undergoing a simple titration schedule might minimize the risk of DRESS.”

SK Life Science recently announced in March that cenobamate had been designated as a Schedule V agent by the DEA, the lowest designation for abuse from the agency. The FDA originally granted approval to cenobamate for the treatment of partial-onset seizures in adults in November 2019.^4,5

REFERENCES

1. Results of a randomized study showing that adjunctive cenobamate significantly improved seizure control in adults with uncontrolled focal seizures published in Neurology [news release]. Zug, Switzerland: Arvelle Therapeutics. Published May 21, 2020. Accessed June 1, 2020. globenewswire.com/news-release/2020/05/21/2036784/0/en/Results-of-a-Randomised-Study-Showing-that-Adjunctive-Cenobamate-Significantly-Improved-Seizure-control-in-Adults-with-Uncontrolled-Focal-Seizures-Published-in-Neurology-1.html

2. Chung SS, French JA, Kowalski J, at al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology. Published online May 14, 2020. doi: 10.1212/WNL.0000000000009530.

3. Sperling MR, Klein P, Aboumatar S, et al. Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study. Epilepsia. Published online May 12, 2020. doi: 10.1111/epi.16525.

4. SK life science Receives Schedule V Designation from DEA for XCOPRI® (cenobamate tablets) [press release]. Paramus, NJ: Published March 10, 2020. Accessed March 10, 2020. prnewswire.com/news-releases/sk-life-science-receives-schedule-v-designation-from-dea-for-xcopri-cenobamate-tablets-301020783.html

5. FDA approves new treatment for adults with partial-onset seizures [press release]. Silver Spring, MD: FDA; Published November 21, 2019. Accessed June 2, 2020. fda.gov/news-events/press-announcements/fda-approves-new-treatment-adults-partial-onset-seizures.