2026-07-11 | Carisbamate treatment of adult and pediatric patients with Lennox-Gastaut syndrome: A phase 1 pharmacokinetic, safety, and tolerability study.

To characterize the single- and multiple-dose pharmacokinetics, safety, and tolerability of carisbamate oral suspension in adult and pediatric patients with Lennox-Gastaut syndrome (LGS). This phase 1, open-label study (NCT03731715) enrolled patients into four age cohorts: Cohort I (C-I), ≥ 18 years; Cohort II (C-II), 12 to < 18 years; Cohort III (C-III), 6 to < 12 years; Cohort IV (C-IV), 2 to < 6 years (C-IV withdrawn due to inability to enroll patients). On Day 1, patients received a single dose of carisbamate: 200 mg (C-I), 140 mg (C-II), 60 mg (C-III), followed by twice-daily multiple-dosing Days 3-17: 100 mg (C-I), 70 mg (C-II), 30 mg (C-III). Pharmacokinetic parameters were determined using noncompartmental analysis. Safety was also assessed. Eighteen patients (C-I: n = 8; C-II: n = 3; C-III: n = 7) were included; 16 (89%) completed the study. Following single doses, carisbamate was rapidly absorbed (tmax, 1-2 h post-dose), with a mean t1/2 of ∼12 h in C-I and C-II and ∼8 h in C-III. After single- and multiple-doses, mean Cmax, AUC0-last, and AUC0-inf increased dose-proportionally. Total carisbamate exposures were comparable across cohorts after dose normalization. Mean (SD) accumulation ratios following multiple dosing were 1.66 (0.15; C-I) and 1.69 (0.06; C-II). Treatment-emergent adverse events (TEAEs) occurred in 66.7% of patients, most commonly nervous system TEAEs (22.2%). One severe TEAE (affective disorder) occurred, and one patient discontinued due to an AE (sedation). No serious TEAEs or deaths occurred. In this small phase 1 PK/safety study, carisbamate appeared to exhibit linear, dose-proportional pharmacokinetic parameters in pediatric and adult LGS patients at doses of 60-200 mg/day and was generally well tolerated during short-term treatment.

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2026-07-05 | Prolonged fenfluramine use in open-label studies of Dravet or Lennox-Gastaut syndromes: Long-term safety, tolerability, patient global functioning, and considerations for interpreting effectiveness.

Long-term safety and global functioning are reported in patients with Dravet syndrome (DS) or Lennox-Gastaut syndrome (LGS) treated with fenfluramine in an open-label extension (OLE) study after participating in a previous open-label feeder study. Patients could enroll in this international, multicenter OLE (NCT03936777) after completing one of three fenfluramine open-label studies. The latest feeder study fenfluramine dose was continued, then flexibly titrated (maximum: .7 mg/kg/day [26 mg/day] without stiripentol or .4 mg/kg/day [17 mg/day] with stiripentol), with ≥1 concomitant antiseizure medication administered. Primary endpoint was fenfluramine long-term safety/tolerability. Global functioning using caregiver- and investigator-reported Clinical Global Impression of Improvement (CGI-I) ratings, globally and for subdomains (cognition, behavior, motor function), at last visit relative to study baseline was evaluated. Overall treatment exposure and age groups were analyzed post hoc. A total of 412 patients enrolled (DS: 265 [64.3%], LGS: 147 [35.7%]); 30.8% were ≥18 years old. Median fenfluramine treatment duration in this OLE was 729.5 days (range = 8-1544), and overall median fenfluramine exposure, including feeder studies, was 1464.5 days (range = 171-2800). In this OLE, ≥1 treatment-emergent adverse event (TEAE) was reported in 311 (75.5%) patients; fenfluramine-related (per investigator) serious TEAEs were reported in five (1.2%) patients. Three patients died in this OLE (deemed unrelated to fenfluramine by investigators). After starting this OLE already receiving fenfluramine, 373 of 401 (93.0%) and 376 of 401 (93.8%) patients were rated by caregiver and investigator, respectively, as "improved or no change" on CGI-I versus this study baseline; subdomain ratings of "improved or no change" were largely consistent with global assessment. In our OLE study of patients with DS or LGS treated with fenfluramine (up to 4 years), no new or unexpected safety signals were observed; global functioning was improved or stable (vs. study baseline) in >90% of patients, supporting long-term fenfluramine use in pediatric and adult patients with DS or LGS.

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2026-07-02 | Fenfluramine for seizures in Dravet syndrome and Lennox-Gastaut syndrome: Mechanisms, clinical evidence, safety, and practical integration.

Developmental and epileptic encephalopathies such as Dravet syndrome and Lennox-Gastaut syndrome remain highly drug resistant and are associated with substantial neurodevelopmental, behavioral, and caregiver burdens. Fenfluramine, repurposed at low antiseizure doses, is approved as adjunctive therapy for both syndromes and has a distinct multimodal mechanism that combines serotonergic modulation with positive allosteric activity at the sigma-1 receptor. This narrative review summarizes key translational insights and the pivotal clinical trial evidence in Dravet syndrome and Lennox-Gastaut syndrome, including long-term open-label extension and emerging real-world data. Across randomized studies, fenfluramine reduces convulsive seizures in Dravet syndrome and drop seizures in Lennox-Gastaut syndrome, with clinically meaningful responder rates and durability over time. Particular attention is given to neurocognitive and behavioral outcomes, as caregiver-reported improvements in executive function have been observed in Dravet cohorts and may not be fully explained by seizure reduction alone. Given historical associations between high-dose fenfluramine and cardiopulmonary adverse effects, we also review cardiovascular safety findings at antiseizure doses and the rationale for baseline and periodic echocardiographic monitoring. Finally, practical dosing, drug-drug interaction considerations, and an integration algorithm are provided to support routine clinical implementation across pediatric and adult care pathways.

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