Adjunctive Cenobamate for Focal-Onset Seizures in Adults: A Systematic Review and Meta-Analysis

Abstract

Background: Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. This drug can enhance the inactivated state of voltage-gated sodium channels, preferentially inhibiting the persistent component of the sodium channel current, and acts as a positive allosteric modulator of GABA_A receptors, binding at a non-benzodiazepine site.

Objective: We assessed the efficacy and safety of adjunctive cenobamate for the treatment of focal-onset seizures in adult patients with epilepsy using meta-analytical techniques.

Methods: We systematically searched (May, week 4, 2020) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ). There were no date limitations or language restrictions. Randomized, placebo-controlled, single or double-blinded, add-on trials of cenobamate in adult patients with uncontrolled focal-onset seizures were identified. Main outcomes included the proportion of patients with ≥ 50 and 100% reduction in seizure frequency during the maintenance treatment period compared with baseline and the incidence of treatment withdrawal and adverse events (AEs). Risk ratio (RR) with 95% confidence interval (CI) was estimated for each outcome.

Results: Two trials were included, overall enrolling 659 patients (442 for the add-on cenobamate group and 217 for the add-on placebo group). Seizure frequency reduction by at least 50% occurred during the maintenance phase in 50.1% of the patients randomized to cenobamate and 23.5% of the placebo-treated participants (RR 2.18, 95% CI 1.67-2.85; p < 0.001). The pooled estimated RR to achieve seizure freedom for the cenobamate group in comparison with placebo was 3.71 (95% CI 1.93-7.14; p < 0.001). Withdrawal from randomized treatment occurred in 16.7 and 11.1% of participants receiving cenobamate and placebo, respectively (RR 1.34, 95% CI 0.85-2.09; p = 0.205). Treatment was discontinued due to AEs in 12.2 and 4.1% of the patients in the active and control arms (RR 2.27, 95% CI 1.08-4.79; p = 0.031). AEs were reported in 76.9 and 66.8% of the patients during treatment with cenobamate and placebo (RR 1.14, 95% CI 1.02-1.26; p = 0.021). The cenobamate-associated AEs included somnolence, dizziness, fatigue, balance disorder, and diplopia.

Conclusions: Adjunctive cenobamate in adult patients with uncontrolled focal-onset seizures is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

Fig. 1

Flow diagram of study selection process. CENTRAL Cochrane Central Register of Controlled Trials

Fig. 2

Fifty percent or greater reduction in baseline seizure frequency during the treatment maintenance period. a Cenobamate any dose, b cenobamate 100 mg/day, c cenobamate 200 mg/day, d cenobamate 400 mg/day. Risk ratios are from a fixed-effects model. CI confidence interval, CNB cenobamate

Fig. 3

Seventy-five percent or greater reduction in baseline seizure frequency during the treatment maintenance period. a Cenobamate any dose, b cenobamate 100 mg/day, c cenobamate 200 mg/day, d cenobamate 400 mg/day. Risk ratios are from a fixed-effects model. CI confidence interval, CNB cenobamate

Fig. 4

Ninety percent or greater reduction in baseline seizure frequency during the treatment maintenance period. a Cenobamate any dose, b cenobamate 100 mg/day, c cenobamate 200 mg/day. d cenobamate 400 mg/day. Risk ratios are from a fixed-effects model. CI confidence interval, CNB cenobamate

Fig. 5

Seizure freedom during the treatment maintenance period. a Cenobamate any dose, b cenobamate 100 mg/day, c cenobamate 200 mg/day, d cenobamate 400 mg/day. Risk ratios are from a fixed-effects model. CI confidence interval, CNB cenobamate