Table 1.

Summary of Studies.

Study Type	Author	Groups Studied and Intervention	Results and Findings	Conclusions
Multicenter, single-blind, placebo controlled clinical trial	Kasteleijn-Nolst Trenite et al.	Adults with photosensitive epilepsy underwent intermittent photic therapy after given a single dose of either placebo, 100 mg, 250 mg, or 400 mg cenobamate to assess efficacy, pharmacokinetics, and safety of cenobamate.	Photoparoxysmal-EEG response was reduced with the 250 mg and 400 mg doses of cenobamate compared to the placebo. Plasma concentration values of 201 to 400 measured by area under the plasma concentration-time curve resulted in partial suppression in 4 of 6 (66%) of patients. Furthermore, there were no deaths or serious treatment emergent adverse events that led to discontinuation in this study.	Cenobamate is a possible efficacious therapy in epilepsy, given that it suppressed IPS-PPR response in patients with photosensitive epilepsy. Additionally results demonstrated that cenobamate was well tolerated in doses up to 400 mg.
Multicenter, double blind, placebo-controlled clinical trial	Chung et al.	Two hundred and twenty-two patients with focal seizures and ages from 18–65 were randomized and grouped into a treatment or placebo group. The study lasted 12 weeks and consisted of a 6 week titration and 6 week maintenance phase. Dose of cenobamate was started as 50 mg/d, and eventually titrated up to 200 mg for the maintenance phase.	When compared to the placebo, cenobamate had a greater median percent seizure reduction (55.6% vs. 21.5%, p < 0.0001). Of the patients in the treatment group, 28.3% were seizure free in the maintenance phase,. 8.8% in the placebo group were seizure free in the maintenance phase. The most common side effects were somnolence, dizziness, headache, nausea, and fatigue.	When compared to a placebo group, adjunctive therapy with cenobamate significantly improved seizure control in adults with uncontrolled focal seizures and treatment was well tolerated.
Multicenter, double-blind, placebo-controlled, dose-response clinical trial	Krauss et al.	Adults from ages 18–70 with focal seizures were assigned to adjuvant once daily oral cenobamate doses of 100 mg, 200 mg, 400 mg, or placebo. There was a 6-week titration phase to titrate patients to assigned doses and a 6 week maintenance phase.	Median percentage changes in seizure frequency were −24.0% (IQR −45.0 to −7.0%) for the placebo group compared with −35·5% (−62.5 to −15.0%; p = 0·0071) for the 100 mg dose group, −55.0% (−73.0 to −23.0%; p < 0·0001) for the 200 mg dose group, and −55.0% (−85.0 to −28.0%; p < 0.0001) for the 400 mg dose group. Treatment-emergent adverse events occurred more frequently with increasing doses: 70% of patients in the placebo group, 65% in the 100 mg group, 76% in the 200 mg group, and 90% in the 400 mg group. One serious case of DRESS and systemic symptoms occurred in the 200 mg group.	Adjunctive cenobamate is efficacious in reducing focal onset seizures in a dose related fashion. However, treatment-emergent events appear to also increase in a dose-related fasion.
Ongoing open label extension of the YKP3089C013	Chung, French, Krauss, et al.	Patients who completed a double-blind placebo-controlled study enrolled in an open label extension. They were either tapered off the study drug before transitioning to open label treatment or allowed to directly enter without initial tapering. The maximum dose was 400 mg.	Median duration of adjunctive cenobamate exposure was 60.6 months and the median modal daily dose was 200 mg. At the time of analysis, 57.5% remained in the extension. Reasons for discontinuation overall were withdrawal by patient (18.8%), adverse events (9.4%), other (8.7%), and lost to follow-up (2.7%).	In 58% of patients, adjunctive cenobamate was generally well tolerated with long-term treatment.
Whole-cell patch recordings and a patch-clamp amplifier electrophysiology	Nakamura et al.	Rat hippocampal CA3 neurons were isolated to study the effects of cenobamate on voltage gated Na+ channels	Cenobamate inhibited the non-inactivating persistent component of INa (INaP). In addition, cenobamate binds to voltage-gated Na+ channels at the inactivated state with a higher affinity. Cenobamate also accelerated the development of inactivation and stunted recovery from inactivation of voltage-gated Na+ channels Cenobamate also increased the threshold for generation of action potentials, and decreased the number of action potentials elicited by depolarizing current injection.	whole-cell patch recordings and a patch-clamp amplifier electrophysiology
Radioligand binding displacement assay	Sharma et al	rat hippocampal CA3 neurons, rat dentate gyrus granule cells (DGGCs), and mouse and rat hippocampal CA1 neurons were studied. Radioligand binding displacement assays were conducted to assess the binding of cenobamate on GABAA receptor sites. Potentiation of GABA-induced currents, as well as effects on both phasic and tonic GABAA currents Were obtained by Electrophysiological recordings	Cenobamate did not significantly displace the binding of GABA, muscimol, flunitrazepam, or Ro-15-1788 (flumazenil) to GABAA receptors. Cenobamate significantly displaced the binding of TBPS radioligand to GABA-gated Cl- channel. In rat hippocampal CA3 neurons, cenobamate (≥30 μM) significantly enhanced GABA-induced current (EC50 = 164 μM). the potentiation of GABA-induced currents by cenobamate was not affected by flumazenil. In mouse CA1 neurons, cenobamate significantly delayed the decay of evoked inhibitory postsynaptic currents without altering the peak amplitude. Cenobamate also enhanced tonic GABAA currents in a concentration-dependent manner in rat CA1 neurons and DGGCs	Radioligand binding displacement assay