Amelie Lothe, PhD, discusses long-term results of fenfluramine for Lennox-Gastaut syndrome

Long-term treatment with fenfluramine was associated with sustained reductions in seizure frequency and stable cardiovascular safety in children and adults with Lennox-Gastaut syndrome (LGS), according to final results from an open-label extension (OLE) study published in Epilepsy & Behavior.

The OLE followed a prior randomized, double-blind, placebo-controlled trial and enrolled 247 patients aged 2 to 35 years with confirmed LGS who had not experienced clinically meaningful seizure worsening at trial completion. As Amelie Lothe, PhD, explained, “Given that LGS is a lifelong condition, understanding the long-term treatment response is critical for families, but also for clinicians.” The primary objectives were to assess long-term safety and tolerability and to evaluate the durability of effect, including outcomes not typically captured in short-term trials.

Patients initiated fenfluramine at 0.2 mg/kg/day, with titration up to 0.7 mg/kg/day (maximum 26 mg/day) based on clinical response and tolerability. The mean daily dose across the study was 0.4 mg/kg/day. Lothe noted that “adults often received this maximum dose,” and that dosing reflected approved prescribing information in the United States.

The enrolled population reflected severe disease burden. The median number of prior antiseizure medications (ASMs) was seven, and patients were taking a median of three concomitant ASMs at baseline. Lothe emphasized, “the real world LGS population was very severe,” underscoring the refractory nature of the cohort.

From month 2 to the end of study, the median percentage reduction in seizures associated with a fall was 31.1% (P < .0001). Reductions were observed in both pediatric (−27.6%) and adult (−40.0%) subgroups. Lothe highlighted that “50% of patients experience seven consecutive seizure-free days,” describing this as “a very meaningful outcome for families.”

Generalized tonic-clonic seizures (GTCS) were among the most responsive seizure types. As Lothe stated, “the generalized tonic clonic seizures were most responsive to treatment with fenfluramine, with a median reduction of 47% over the entire open-label extension.” Given that GTCS are associated with injury and represent a major risk factor for sudden unexpected death in epilepsy, these findings may have clinical relevance.

Safety findings were consistent with prior reports. Treatment-emergent adverse events occurred in 83.0% of patients, most commonly decreased appetite, fatigue, nasopharyngitis, seizure, and pyrexia. No cases of valvular heart disease or pulmonary arterial hypertension were identified on echocardiographic monitoring.

Beyond seizure reduction, global functioning and quality-of-life measures improved. At the last visit, 59.9% of caregivers and 57.0% of investigators rated patients as improved on the Clinical Global Impression–Improvement scale. Mean overall Quality of Life in Childhood Epilepsy scores improved at Month 12 (mean change, 2.9 points; P = .0166). Caregiver anxiety scores on the Hospital Anxiety and Depression Scale also showed statistically significant improvement.

“The main takeaway of this study is the fact that fenfluramine demonstrates a sustained efficacy and tolerability over the long term,” Lothe said, adding that these data reinforce the treatment’s benefit-risk profile in patients 2 years and older with LGS. She further noted that “LGS is more than seizures,” emphasizing the importance of multidisciplinary care and attention to developmental, behavioral, and psychosocial challenges.

For general pediatricians, Lothe underscored the importance of early recognition, coordinated care, and collaboration with epilepsy specialists. “Continuity of care” remains central in managing this chronic developmental and epileptic encephalopathy, she said.

Disclosure

The study was sponsored by UCB, and Lothe reports being an employee of UCB.

Reference

Knupp KG, Scheffer IE, Schoonjans AS, et al. Final analysis from an open-label extension study of fenfluramine for the treatment of seizures in Lennox-Gastaut syndrome: long-term impact on patients and caregivers. Epilepsy Behav. 2025;173:110753. doi:10.1016/j.yebeh.2025.110753