piperidines and Spasms--Infantile

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

Infantile spasm syndrome (ISS) is an epileptic encephalopathy without established treatment after the failure to standard of care based on steroids and vigabatrin. Converging lines of evidence indicating a role of NR2B subunits of the N-methyl-D-aspartate (NMDA) receptor on the onset of spams in ISS patients, prompted us to test radiprodil, a negative allosteric NR2B modulator in preclinical seizure models and in infants with ISS.. Radiprodil has been tested in three models, including pentylenetetrazole-induced seizures in rats across different postnatal (PN) ages. Three infants with ISS have been included in a phase 1b escalating repeated dose study.. Radiprodil showed the largest protective seizure effects in juvenile rats (maximum at PN12, corresponding to late infancy in humans). Three infants resistant to a combination of vigabatrin and prednisolone received individually titrated doses of radiprodil for up to 34 days. Radiprodil was safe and well tolerated in all three infants, and showed the expected pharmacokinetic profile. One infant became spasm-free and two showed clinical improvement without reaching spasm-freedom. After radiprodil withdrawal, the one infant continued to be spasm-free, while the two others experienced seizure worsening requiring the use of the ketogenic diet and other antiepileptic drugs.. Radiprodil showed prominent anti-seizure effect in juvenile animals, consistent with the prevalent expression of NR2B subunit of the NMDA receptor at this age in both rodents and humans. The clinical testing, although preliminary, showed that radiprodil is associated with a good safety and pharmacokinetic profile, and with the potential to control epileptic spasms.

Topics: Acetamides; Animals; Anticonvulsants; Disease Models, Animal; Drug Resistant Epilepsy; Female; Humans; Infant; Male; Mice; Outcome Assessment, Health Care; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Spasms, Infantile

Topics: Cerebral Palsy; Child; Child, Preschool; Chlorpromazine; Epilepsy; Epilepsy, Absence; Glutamates; Humans; Infant; Infant, Newborn; Intellectual Disability; Muscles; Piperidines; Pyridoxine; Reserpine; RNA; Spasms, Infantile