Approximately one‐third of people living with epilepsy are unable to obtain seizure control with the currently marketed antiseizure medications (ASMs), creating a need for novel therapeutics with new mechanisms of action. Cenobamate (CBM) is a tetrazole alkyl carbamate derivative that received US Food and Drug Administration approval in 2019 for the treatment of adult partial onset (focal) seizures. Although CBM displayed impressive seizure reduction in clinical trials across all seizure types, including focal aware motor, focal impaired awareness, and focal to bilateral tonic‐clonic seizures, the precise mechanism(s) through which CBM exerts its broad‐spectrum antiseizure effects is not known. Experimental evidence suggests that CBM differentiates itself from other ASMs in that it appears to possess dual modes of action (MOAs); that is, it predominately blocks persistent sodium currents and increases both phasic and tonic γ‐aminobutyric acid (GABA) inhibition. In this review, we analyze the preclinical efficacy of CBM alongside ASMs with similar MOAs to better understand the mechanism(s) through which CBM achieves such broad‐spectrum seizure protection. CBM’s preclinical performance in tests, including the mouse 6‐Hz model of treatment‐resistant seizures, the chemoconvulsant seizure models of generalized epilepsy, and the rat hippocampal kindling model of focal epilepsy, was distinct from other voltage‐gated sodium channel blockers and GABAA modulators. This distinction, in light of its proposed mechanism(s) of action, provides insight into the impressive clinical efficacy of CBM in the adult patient with focal onset epilepsy. The results of this comparative reverse translational analysis suggest that CBM is a mechanistically distinct ASM that offers an important advancement in drug development for treatment of therapy‐resistant epilepsy.

中文翻译：

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Cenobamate (XCOPRI)：临床前和临床证据能否深入了解其作用机制？

大约三分之一的癫痫患者无法通过目前上市的抗癫痫药物 (ASM) 控制癫痫发作，因此需要具有新作用机制的新型疗法。Cenobamate (CBM) 是一种四唑烷基氨基甲酸酯衍生物，于 2019 年获得美国食品和药物管理局的批准，用于治疗成人部分发作（局灶性）癫痫发作。尽管 CBM 在所有癫痫发作类型的临床试验中显示出令人印象深刻的癫痫发作减少，包括局灶性意识运动、局灶性意识障碍和局灶性双侧强直阵挛发作，但 CBM 发挥其广谱抗癫痫作用的确切机制尚不清楚已知。实验证据表明，CBM 与其他 ASM 的区别在于它似乎具有双重作用模式 (MOA)；那是，它主要阻断持续的钠电流并增加相位和滋补γ-氨基丁酸（GABA）的抑制作用。在这篇综述中，我们分析了 CBM 与具有类似 MOA 的 ASM 的临床前疗效，以更好地了解 CBM 实现这种广谱癫痫保护的机制。CBM 在测试中的临床前性能，包括小鼠 6-Hz 抗治疗癫痫模型、全身性癫痫的化学惊厥发作模型和局灶性癫痫的大鼠海马点燃模型，与其他电压门控钠通道阻滞剂和 GABAA 调节剂不同. 根据其提议的作用机制，这种区别提供了对 CBM 在成年局灶性癫痫患者中令人印象深刻的临床疗效的见解。