Efficacy, safety and tolerability of adjunctive cenobamate in pediatric and adult patients with Lennox Gastaut Syndrome.

Lennox-Gastaut Syndrome (LGS) is a severe developmental epileptic encephalopathy of childhood consisting of a triad of drug refractory epilepsy with multiple seizure types, cognitive impairment, and a characteristic electroencephalogram (EEG). Cenobamate (CNB) is a novel antiseizure medication (ASM) effective against focal epilepsy. Proposed mechanisms of action include inactivation of persistent sodium currents and weak positive allosteric modulation of synaptic (phasic) and extrasynaptic (tonic) GABAA receptors. This is a single center study 16 LGS patients receiving CNB (F = 6, pediatric 8, median age 20y (range 9-38). Mean CNB exposure was 735 days with 81 % (13/16) continuing CNB at last follow up. RR was > 50 % in 75 % (12/16), >75 % in 56 % (916), > 90 % in 38 % (6/16) and 100 % in 31 % (5/16) of patients. Duration of seizure freedom at the time of the data analysis ranged from 107 - 681 days, with 3/16 (19 %) seizure free for > 6 months, including 2 (13 %) for 1 year. Seizure frequency increased in three patients. In all three, there was an initial seizure improvement at lower doses of up to 50 mg/d, followed by seizure exacerbation at doses up to 350 mg/d, with return to baseline after dose reduction. Safety and Tolerability (n = 16): 44 % patients (n = 7) developed TEAEs: somnolence (n = 5, 31.25 %), ataxia (n = 2, 12.5 %), aggression/agitation (n = 2, 12.5 %), and one (6.25 %) each dizziness, headache, blurry vision and insomnia. 4 patients had more than one reported AE. Positive side effects (cognition, behavior, verbal communication, mood, sleep) were reported in 63 % (10/16). 44 % patients (n = 7) developed TEAEs: somnolence (5), insomnia (1), ataxia (2), dizziness (1), aggression/agitation (2), and headache with blurry vision (1). 19 % (n = 3) discontinued due to TEAE (somnolence n = 2 and increased seizures (n = 3). TEAEs were generally mild to moderate. Post-CNB EEG were available for 5 patients (aged 9-18 yrs) and showed no change in one patient, partial improvement in 2 patients and complete remission of interictal epileptiform discharges (IEDs) in 2 patients. Our data suggest promising efficacy and good tolerability of adjunctive CNB treatment in LGS patients with varied etiologies. A prospective randomized controlled study of cenobamate in LGS patients is warranted.