Fenfluramine shows sustained seizure reduction, functional improvement in Lennox-Gastaut syndrome

Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy characterized by multiple seizure types, developmental delay, and cognitive and behavioral difficulties that can persist into adulthood. Treatment often requires multiple antiseizure medications, with fenfluramine among the adjunctive therapies available for seizure management.^1,2

A 2026 post hoc analysis published in Epilepsia Open examined the trajectory of effectiveness and safety of fenfluramine among patients with LGS who participated in a phase 3 randomized controlled trial and its open-label extension. The analysis included 151 patients who completed 12 months of the extension study, including 59 who transitioned from placebo to fenfluramine and 92 who received fenfluramine during both the randomized trial and extension. Investigators found rapid improvements after fenfluramine initiation, with patients transitioning from placebo experiencing a 32.1% median reduction from baseline in seizures associated with a fall by month 1. Reductions continued as the mean fenfluramine dose increased, reaching 48.2% over months 4 through 6.

Improvements extended beyond seizure frequency. By month 12, 52.6% of patients who transitioned from placebo were rated by parents or caregivers as having clinically meaningful improvement in global functioning, while 46.3% received that rating from investigators. In the following Q&A, Contemporary Pediatrics spoke with Amélie Lothe, PhD, Global Medical Community Head for developmental and epileptic encephalopathies/neurodevelopmental disorders at UCB and an investigator on the study, about what the findings mean for pediatric practice, including expectations for early response, dose titration, monitoring adverse events, and assessing improvements beyond seizure counts.

Contemporary Pediatrics: For pediatricians caring for children with Lennox-Gastaut syndrome, what do these findings suggest about how soon families may begin to see a response after starting fenfluramine?

Amélie Lothe, PhD: This post-hoc analysis showed rapid and sustained improvement in seizure frequency and global functioning in children and adults with LGS ranging from 2 to 35 years of age at study entry who transitioned from placebo to FINTEPLA (fenfluramine), as well as those who continued FINTEPLA treatment, throughout both the original randomized controlled trial (RCT) and open-label extension (OLE). Study participants who transitioned from placebo to FINTEPLA in the open-label extension experienced a reduction in seizure frequency as early as one month after FINTEPLA initiation, with a −32.1% median reduction in seizures associated with a fall compared with baseline. These benefits continued to build over time as the FINTEPLA dose was optimized, with greater seizure reductions and improvements in global functioning observed following dose titration.

For pediatricians, this means that meaningful change may begin within the first month of treatment, which can offer real reassurance during a period that’s otherwise filled with uncertainty. These findings can help clinicians and families better understand the expected course of FINTEPLA treatment, and guide discussions about early response, dose optimization, and the potential benefits of continued therapy.

Contemporary Pediatrics: The analysis showed that seizure frequency continued to improve as the mean fenfluramine dose increased. How should clinicians think about dose titration and the amount of time needed to adequately assess treatment response in pediatric patients?

Lothe: In this analysis, the mean FINTEPLA dose increased steadily to 0.5 mg/kg/day by Month 4, and effectiveness continued to improve in parallel — seizure reductions reached −48.2% over Months 4–6 in patients who had transitioned from placebo, similar to the −44.2% reduction seen in that same window among patients treated with FINTEPLA from the start. Improvements in global functioning were also observed over time.

That pattern suggests that early response may not tell the full story. As doses are optimized for the individual child, additional benefits may continue to emerge.

Based on these findings, we believe assessment of FINTEPLA effectiveness should extend to at least 4 months of treatment where possible, allowing adequate time for dose optimization and continued treatment before drawing conclusions about response. It is also worth noting that titration in this open-label study was not standardized and may differ somewhat from routine clinical practice. For patients not receiving stiripentol, FINTEPLA can be titrated to a maximum of 0.7 mg/kg/day, up to 26 mg/day. Working closely with the care team to identify each child’s optimal, tolerated dose remains essential.

Contemporary Pediatrics: Beyond seizure reduction, both caregivers and investigators reported improvements in global functioning. What might these improvements look like in a child’s daily life, and what should pediatricians ask families about when assessing whether treatment is benefiting the child overall

Lothe: Clinically meaningful improvements in global functioning were assessed using the Clinical Global Impression–Improvement (CGI-I) scale, in which parent/caregiver and investigator ratings of ‘much improved’ or ‘very much improved’ relative to baseline were considered clinically meaningful for both parent/caregiver and investigator assessments. These improvements were observed shortly after patients initiated FINTEPLA.

This kind of improvement can look different for every child. For example, some families reported that their loved one became more engaged in everyday activities.

By Month 12, 52.6% and 46.3% of patients who had transitioned from placebo were rated as demonstrating clinically meaningful improvement by parent/caregiver and investigator, respectively, with similar improvements observed among patients treated with FINTEPLA from the start (50.0% and 50.5%, respectively).

This is a good reminder for pediatricians to ask families not just about seizure counts, but also about other relevant LGS symptoms and day-to-day functioning at each visit — since meaningful benefit may be showing up in ways that are not captured by the seizure diary.

Contemporary Pediatrics: Decreased appetite, somnolence, fatigue, and diarrhea were among the adverse events that increased after treatment initiation but generally declined over time. What should pediatricians know about monitoring these effects, particularly when it comes to growth, nutrition, development, and day-to-day functioning?

Lothe: Safety findings in this analysis were consistent with the known safety profile of FINTEPLA, and overall, FINTEPLA was generally well tolerated during long-term treatment. The incidence of commonly reported treatment-emergent adverse events, including decreased appetite, somnolence, fatigue, and diarrhea, increased around treatment initiation but generally decreased over time with continued treatment, supporting the long-term tolerability of FINTEPLA.

Data from clinical trials and real-world studies also show that in the vast majority of patients, decreased appetite does not lead to FINTEPLA discontinuation and resolves over time without necessarily translating to weight loss.

For pediatricians, this means preparing families for potential adverse events at initiation, while continuing to monitor weight and growth regularly throughout treatment, consistent with FINTEPLA’s prescribing information. Overall, these results provide further confidence in the long-term benefit-risk profile of FINTEPLA for people living with Lennox-Gastaut syndrome.

Contemporary Pediatrics: Many children with Lennox-Gastaut syndrome have complex treatment histories and take multiple antiseizure medications. How might these findings help pediatricians and pediatric neurologists counsel families about expectations when fenfluramine is added to a child’s treatment regimen?

Lothe: Families managing LGS often arrive at FINTEPLA after a long history of prior antiseizure medications, and many children remain on multiple concomitant therapies once it’s added. The first few months after starting a new treatment option are often a time of uncertainty for both clinicians and families. One of the key questions is: When can we expect to see improvements, and how might it evolve over time?

These findings give pediatricians clear, evidence-based information to share with families: sustained FINTEPLA treatment is effective and generally well tolerated, with improvements in seizure frequency and global functioning emerging as early as the first month after treatment initiation and continuing to develop over subsequent months as patients undergo dose titration and the mean FINTEPLA dose increases. This can help set realistic expectations, encouraging families to give treatment adequate time to work, to work closely with their care team through dose titration, and to know that early side effects are common and often ease with continued treatment.

References

1. Nabbout R, Devinsky O, Lagae L, et al. Changes in effectiveness and safety in patients with Lennox-Gastaut syndrome transitioning from the fenfluramine randomized controlled trial to open-label extension study. Epilepsia Open. Published online August 3, 2026. doi:10.1002/epi4.70320

2. UCB. Epilepsia Open publishes results of post hoc data analysis of FINTEPLA® (fenfluramine) in patients with Lennox-Gastaut syndrome. PR Newswire. Press Release. August 5, 2026. Accessed September 21, 2026. https://www.prnewswire.com/news-releases/epilepsia-open-publishes-results-of-post-hoc-data-analysis-of-fintepla-fenfluramine-in-patients-with-lennox-gastaut-syndrome-302843865.html?tc=eml_cleartime