Epilepsy Essentials: Cenobamate

ARTICLE UPDATED ON NOVEMBER 22, 2019

People living with epilepsy continue to experience uncontrolled seizures despite available therapies. The search for novel medications and therapies to be used alone or in conjunction with existing agents is ongoing. Cenobamate, formerly identified as YKP3089, was approved by the Food and Drug Administration (FDA) on  November 21, 2019 as an adjunctive antiepileptic drug for epilepsy of focal onset. Cenobamate is of interest because it has broad-spectrum anticonvulsant activity demonstrated in rodent models.¹ Cenobamate may also have utility in treating anxiety and chronic pain.¹

Mechanism of Action and Pharmacokinetics

As with many antiepileptic drugs, the exact mechanism for cenobamate remains unclear. There are 2 primary mechanisms of action proposed. Cenobamate is thought to enhance inhibition through modulation of GABA_A channels and decrease excitatory currents by inhibiting sodium currents. Activity at GABA_A channels has been reported as a nonbenzodiazepine type positive allosteric modulator of the GABA_A receptor, resulting in increased inhibition and enhancement of GABA_A receptor-mediated currents.² Cenobamate is thought to modulate voltage-gated sodium ion channels predominantly via inhibition of persistent current.^2,3 Through that inhibition, cenobamate causes a hyperpolarized membrane potential, which has been demonstrated to occur in a concentration-dependent manner.³ Unlike many other antiepileptic drugs currently in use, however, cenobamate has little effect on the peak component of transient sodium current.³ The effect on membrane potential thus seems to occur through activation of a binding site different from that of typical sodium channel agents.¹

Results of Clinical Trials to Date

As a drug in development, experience with cenobamate is limited, but the agent shows promise. Cenobamate decreased the photoparoxysmal-EEG response sensitivity in a small multicenter single-blind study of adults with photosensitive epilepsy. The study also demonstrated increasing suppression of intermittent photostimulation responses observed with higher doses of cenobamate.⁴ Overall, this study was considered to demonstrate the potential of cenobamate as an agent with utility in the management of epilepsy. Data gathered in subsequent studies continue to show promise.

More recently, an 18-week study composed of a 6-week titration and 12-week maintenance period evaluated cenobamate vs placebo. The study was a randomized placebo-controlled dose-response study designed to assess the safety and efficacy of cenobamate for control of partial-onset seizures. The 437 participants were randomized to adjunctive therapy with cenobamate 100 mg/day, 200 mg/ day, 400 mg/day, or placebo.⁵

Median seizure frequency decreased with all doses of cenobamate by 35.5% for the 100-mg/day dose and 55.0% for the 200-mg/day and 400-mg/day doses.⁵ Also of note, 2 studies reported seizure-free rates of 11% to 28% with the 200-mg dose.⁶ Results of clinical trials to date suggest clinical efficacy may be apparent as early as 2 weeks after a starting dose of 50 mg of cenobamate, suggesting that an adequate clinical trial need not be prolonged.⁷

Reported pharmacokinetics are generally favorable. The observed half-life is 30 to 75 hours, which should allow for once-daily dosing. The maximal concentration (C_max) and area under the curve (AUC) correlate linearly with doses from 50 to 300 mg/day. The pharmacokinetics of cenobamate do not seem to be influenced by diet.¹ Cenobamate is extensively metabolized in humans and primarily eliminated in urine.⁸ Cenobamate will likely require hepatic dosing based on the results of a small study comparing individuals with and without mild or moderate hepatic impairment.⁸ Additionally, a study compared the effect of age on pharmacokinetics in groups of participants, age 18 to 45 years as compared with participants more than age 65. Based on the results of this comparison, it is believed that dose changes for the elderly will likely not be necessary.⁸

Side Effects

Cenobamate has been generally well-tolerated in studies to date.¹ The most common adverse events (AEs) were somnolence, fatigue, and dizziness.^5,9 More significant findings included orthostatic blood pressure drop, and syncope occurred in 1 participant. Drug reaction with eosinophilia and systemic symptoms (DRESS) was reported in 3 of the first 953 participants given cenobamate.^4,9 Following the concerning reports of DRESS, a subsequent multicenter open-label study of people with epilepsy age 18 to 70 years who had uncontrolled partial seizures and were taking 1 to 3 antiepileptic drugs was undertaken. In this study, the participants were given increasing doses of cenobamate at 2-week intervals, which was slower than previously used titration rates. At the time of the study data cutoff, 1,037 participants were exposed to cenobamate for at least 196 days. There were 4 sudden deaths, 3 of which were reported as occurring because of traumatic intracranial hemorrhage (ICH), motor vehicle accident, and respiratory failure; there was no autopsy in the 4th death. No subsequent cases of DRESS were reported.⁹

Food and Drug Administration Approval

The FDA approved the new drug application for cenobamate for the treatment of partial-onset seizures in adults on November 21, 2019.