Generalized seizures in children - Emerging treatments

Ganaxolone

Ganaxolone is a neurosteroid that acts through positive allosteric modulation of gamma-aminobutyric acid A receptor sites. It is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of seizures (in children >2 years of age) associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder, which is associated with both generalized and focal seizures.[148][149]

Soticlestat

Soticlestat is an investigational selective inhibitor of the brain-specific enzyme cholesterol 24-hydroxylase. In a randomized, double-blind, placebo-controlled study including children with Dravet syndrome or Lennox-Gastaut syndrome, soticlestat was associated with statistically significant, clinically meaningful reductions from baseline in median seizure frequency (combined patient population) and in convulsive seizure frequency (Dravet syndrome cohort). Treatment-emergent adverse events were mostly mild or moderate in severity, and their incidence was similar between the soticlestat and placebo groups.[150]

Lorcaserin

Lorcaserin is a selective serotonin receptor (5-HT2C) agonist with receptors limited to the central nervous system. It was previously licensed for the management of obesity, but was withdrawn from the market owing to a safety signal of an increased risk of cancer in a long-term study. It is currently in clinical development for the treatment of epilepsy. One retrospective case series reported that lorcaserin may reduce motor seizures in children and young adults with treatment-resistant epilepsies, including Dravet syndrome and Lennox-Gastaut syndrome.[151] Phase 3 clinical trials are under way to assess the efficacy and safety of lorcaserin as adjunctive treatment for Dravet syndrome.[152]

Carisbamate

Carisbamate has been granted orphan drug designation by the FDA for the potential treatment of seizures associated with Lennox-Gastaut syndrome.[113] Clinical trials are ongoing.[153][154][155]

Ezogabine (XEN496)

XEN496, a novel granular pediatric formulation of ezogabine (a previously discontinued anticonvulsant), is being investigated for the treatment of patients with KCNQ2 developmental and epileptic encephalopathy.[156][157]

Gene therapies

Gene therapies are being investigated for treating Dravet syndrome and Lennox-Gastaut syndrome.[158][159] For example, STK-001 is an antisense oligonucleotide that is intended to increase the level of productive SCN1A mRNA and consequently increase the expression of the sodium channel protein Nav1.1 in patients with Dravet syndrome.[160][161]

Neurostimulation

Deep brain stimulation and responsive neurostimulation therapy have been shown to be effective in adults with refractory epilepsy, but they are not approved for children and evidence in this population is limited.[162][163][164] Noninvasive methods such as transcranial magnetic stimulation and transcranial direct current stimulation are being investigated, but information regarding use for treating generalized seizures is scarce.[165][166]