Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications (ASMs). Although dozens of ASMs are available in the clinic, approximately 30% of epileptic patients have medically refractory seizures; other limitations in most traditional ASMs include poor tolerability and drug-drug interactions. Therefore, there is an urgent need to develop alternative ASMs. Levetiracetam (LEV) is a first-line ASM that is well tolerated, has promising efficacy, and has little drug-drug interaction. Although it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein (SV) 2A, the molecular basis of its action remains unknown. Even so, the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical success. This review highlights the research and development (R&D) process of LEV and its analogs, brivaracetam and padsevonil, to provide ideas and experience for the R&D of novel ASMs.

UNASSIGNED: Epilepsy is a common neurological condition, affecting over 70 million individuals worldwide.
UNASSIGNED: The present paper reviews current and future (under preclinical and clinical development) pharmacotherapy options for the treatment of drug-resistant focal and generalized epilepsies.
UNASSIGNED: Current pharmacotherapy options for drug-resistant epilepsy include perampanel, brivaracetam and the newly approved cenobamate for focal epilepsies; cannabidiol (Epidiolex) for Lennox-Gastaut Syndrome (LGS), Dravet and Tuberous Sclerosis Complex (TSC); fenfluramine for Dravet syndrome and ganaxolone for seizures in Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Many compounds are under clinical development and may hold promise for future pharmacotherapies. For adult focal epilepsies, padsevonil and carisbamate are at a more advanced Phase III stage of clinical development followed by compounds at Phase II like selurampanel, XEN1101 and JNJ-40411813. For specific epilepsy syndromes, XEN 496 is under Phase III development for potassium voltage-gated channel subfamily Q member 2 developmental and epileptic encephalopathy (KCNQ2-DEE), carisbamate is under Phase III development for LGS and Ganaxolone under Phase III development for TSC. Finally, in preclinical models several molecular targets including inhibition of glycolysis, neuroinflammation and sodium channel inhibition have been identified in animal models although further data in animal and later human studies are needed.

Epilepsy is one of the most serious neurological conditions, affecting almost 50 million people around the world. Despite more than 20 antiepileptic drugs (AEDs) available, seizures are still uncontrolled in one third of patients. Areas covered: The present paper reviews current compounds in preclinical and clinical development for the treatment of focal epilepsies and new potential molecular targets recently identified. Expert opinion: 1OP-2198, Cannabidavirin, Everolimus, FV-082, Ganaxolone, Minocycline, NAX 810-2, Padsevonil and Selurampanel seem to be particularly promising in focal epilepsy. Some of them, Everolimus and Ganaxolone, are already completing Phase III development while others are still at a preclinical stage. Everolimus represents the first example of precision-medicine in epilepsy and the first generation of disease-modifying agents but data on long-term safety are needed. Among AEDs in Phase II development, Cannabidavirin, Padsevonil and Selurampanel may represent a promising fourth generation of compounds for focal epilepsies if they successfully proceed to subsequent stages. Data on general tolerability, effects of cognition and behavior as well as the potential for interactions in polytherapy will be key element for the success or decline of these drugs.