ABSTRACT
INTRODUCTION: Despite the existence of over 30 anti-seizure medications (ASM), including 20 over the last 30 years, a third of patients with epilepsy remain refractory to treatment, with no disease-modifying or preventive therapies until very recently. The development of new ASMs with new mechanisms of action is therefore critical. Recent clinical trials of new treatments have shifted focus from traditional common epilepsies to rare, genetic epilepsies with known mechanistic targets for treatment and disease-specific animal models. AREAS COVERED: ASMs in phase 2a/b-3 clinical trials target cholesterol, serotonin, sigma-1 receptors, potassium channels and metabotropic glutamate receptors. Neuroinflammation, protein misfolding, abnormal thalamocortical firing, and molecular deficiencies are among the targeted pathways. Clinically, the current phase 2a/b-3 agents hold promise for variety of epilepsy conditions, from developmental epileptic encephalopathies (Dravet Syndrome, Lennox-Gastaut syndrome, CDKL5 and PCDH19, Rett's Syndrome), infantile spasms, tuberous sclerosis as well as focal and idiopathic generalized epilepsies and acute rescue therapy for cluster seizures. EXPERT OPINION: New delivery mechanisms increase potency and site-specificity of existing drugs. Novel mechanisms of action involve cholesterol degradation, mitochondrial pathways, anti-inflammation, and neuro-regeneration. Earlier identification of genetic conditions through genetic testing will allow for earlier use of disease specific and disease-modifying therapies.
