Expanding the toolkit: An update on the evolution of new therapies for Lennox-Gastaut Syndrome

Lennox-Gastaut Syndrome (LGS) is a severe developmental epileptic encephalopathy (DEE) that develops in response to genetic, traumatic, or other factors. It is defined as a triad of drug refractory epilepsy with multiple seizure types including tonic seizures, cognitive impairment, and signature EEG findings. The dire need for more effective, well-tolerated therapies calls for further innovation and development in oral drug therapies, which remain the cornerstone of LGS management. The purpose of this paper is to address three such aspects of treatment evolution for LGS: (1) To review data supporting the repurposing of existing drugs for use in LGS, specifically, perampanel and cenobamate. (2) To present recent (soticlestat), ongoing (carisbamate, bexicaserin, clemizole) and upcoming (opakalim) clinical drug trials for LGS. (3) To discuss potential future challenges in clinical drug trial development for LGS, including decentralized clinical drug trials and issues related to competing studies. Durable and sustained seizure freedom in LGS has been recently described using newer antiseizure medications, with positive impact on behavior, mood, cognition and verbal communication, with potential weaning of concomitant antiseizure medications. With the richness of recent trial development for LGS combined with the nascence of clinical trials for specific genetic epilepsies comes a new era in which treatment options for LGS will continue to expand. Increasing understanding of the underlying genetic and molecular underpinnings of LGS should enable development of unique therapies, with the continued aims of sustained, durable seizure control and additional positive impact on central nervous system outcomes and beyond.