piperidines and Epilepsies--Myoclonic

Dravet syndrome (DS) is a form of genetic refractory epilepsy. More than 80 % of DS patients carry pathogenic SCN1A mutations, and this percentage is actually higher due to false-negative results in gene testing. Potential genotype-phenotype correlations may exist but require further confirmation. "SCN1A mutation-mediated dysfunction of NaV1.1 affects GABAergic inhibitory interneurons" is currently the most accepted pathogenesis. Besides SCN1A, there are other genes associated with DS-like phenotypes, among which GABA

Topics: Epilepsies, Myoclonic; Humans; NAV1.1 Voltage-Gated Sodium Channel; Piperidines; Quality of Life

Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare treatment-resistant childhood epilepsies classed as developmental and epileptic encephalopathies. ELEKTRA investigated the efficacy and safety of soticlestat (TAK-935) as adjunctive therapy in children with DS or LGS (NCT03650452).. ELEKTRA was a phase 2, randomized, double-blind, placebo-controlled study of soticlestat (≤300 mg twice daily, weight-adjusted) in children (aged 2-17 years) with DS, demonstrating three or more convulsive seizures/month, or with LGS, demonstrating four or more drop seizures/month at baseline. The 20-week treatment period comprised an 8-week dose-optimization period and a 12-week maintenance period. Efficacy endpoints included change from baseline in seizure frequency versus placebo. Safety assessments included incidence of treatment-emergent adverse events (TEAEs).. ELEKTRA enrolled 141 participants; 126 (89%) completed the study. The modified intent-to-treat population included 139 participants who received one or more doses of study drug and had one or more efficacy assessments (DS, n = 51; LGS, n = 88). ELEKTRA achieved its primary endpoint: the combined soticlestat-treated population demonstrated a placebo-adjusted median reduction in seizure frequency of 30.21% during the maintenance period (p = .0008, n = 139). During this period, placebo-adjusted median reductions in convulsive and drop seizure frequencies of 50.00% (p = .0002; patients with DS) and 17.08% (p = .1160; patients with LGS), respectively, were observed. TEAE incidences were similar between the soticlestat (80.3%) and placebo (74.3%) groups and were mostly mild or moderate in severity. Serious TEAEs were reported by 15.5% and 18.6% of participants receiving soticlestat and placebo, respectively. TEAEs reported in soticlestat-treated patients with ≥5% difference from placebo were lethargy and constipation. No deaths were reported.. Soticlestat treatment resulted in statistically significant, clinically meaningful reductions from baseline in median seizure frequency (combined patient population) and in convulsive seizure frequency (DS cohort). Drop seizure frequency showed a nonstatistically significant numerical reduction in children with LGS. Soticlestat had a safety profile consistent with previous studies.

Topics: Anticonvulsants; Child; Double-Blind Method; Epilepsies, Myoclonic; Epileptic Syndromes; Humans; Lennox Gastaut Syndrome; Piperidines; Pyridines; Seizures; Spasms, Infantile; Treatment Outcome

Dravet syndrome is a severe developmental and epileptic encephalopathy (DEE) most often caused by de novo pathogenic variants in SCN1A. Individuals with Dravet syndrome rarely achieve seizure control and have significantly elevated risk for sudden unexplained death in epilepsy (SUDEP). Heterozygous deletion of Scn1a in mice (Scn1a. In this study, the novel compound soticlestat, a CH24H inhibitor, was administered to Scn1a. Soticlestat treatment reduced seizure burden, protected against hyperthermia-induced seizures, and completely prevented SUDEP in Scn1a. This study demonstrates that soticlestat-mediated inhibition of CH24H provides therapeutic benefit for the treatment of Dravet syndrome in mice and has the potential for treatment of DEEs.

Topics: Animals; Cholesterol 24-Hydroxylase; Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Mice; Mortality, Premature; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Piperidines; Pyridines; Seizures; Seizures, Febrile; Sudden Unexpected Death in Epilepsy