Post Hoc Analysis Shows Fenfluramine Treatment Associated With Sustained Seizure Reductions in LGS

A newly published post hoc analysis of a phase 3 study (NCT03355209) and its open-label extension (OLE) in EpilepsiaOpen suggested that treatment with fenfluramine (Fintepla; UCB) was associated with early and sustained reductions in seizures resulting in falls among children and adults with Lennox-Gastaut syndrome (LGS).^1,2

"LGS remains one of the most challenging rare epilepsies to manage, and families and clinicians often have limited visibility into what response may look like in the first months of treatment," Hugo Xi, MD, MBA, Head of Medical for Epilepsy and Rare Syndromes at UCB, said in a statement.² "These findings provide important insight into the treatment trajectory of FINTEPLA, helping inform conversations around early response, dose titration, and the potential value of continued treatment over time."

Fenfluramine is an antiseizure medication currently approved by the FDA for seizures associated with LGS and Dravet syndrome in patients aged 2 years or older. In the study, investigators evaluated patients who completed a 14-week randomized, placebo-controlled phase 3 trial and entered its OLE. Of 263 participants enrolled in the randomized trial, 247 entered the extension; 151 who completed 12 months of extension treatment were included in the post hoc analysis.

Participants were grouped according to whether they switched from placebo to fenfluramine at extension entry (n = 59) or received fenfluramine during both the randomized and extension periods (n = 92). Outcomes included change in the frequency of seizures associated with a fall, improvement on the Clinical Global Impression–Improvement (CGI-I) scale, and treatment-emergent adverse events.

At month 1, the median reduction in seizures associated with a fall was 32.1% from baseline among patients switching from placebo and 48.5% among those continuing fenfluramine. During months 4 through 6, the corresponding median reductions were 48.2% and 44.2%, respectively. Mean fenfluramine doses increased over time, according to the report.

At month 12, 52.6% of patients who switched from placebo were rated “much improved” or “very much improved” by a parent or caregiver, compared with 46.3% by investigator assessment. Among patients continuously treated with fenfluramine, those proportions were 50.0% and 50.5%, respectively.

The incidence of most commonly reported treatment-emergent adverse events in the analysis included decreased appetite, somnolence, fatigue, diarrhea, pyrexia, and nasopharyngitisat. Notably, their incidence increased after fenfluramine initiation in the placebo-switch group and generally declined over continued treatment.

READ MORE: Pediatrics to Adulthood: What the LGS Care Transition is Still Getting Wrong

Findings from a similar post hoc analysis of the study, presented at the 2025 American Epilepsy Society (AES) Annual Meeting, held December 5 to 9, 2025, in Atlanta, Georgia, further confirmed the benefits of fenfluramine and its impact on everyday executive functioning (EEF) in adults with LGS.³ Overall, there was no strong correlation between reductions in fall-associated seizures and improvements in EFF, indicating that these outcomes may be at least partly independent of one another.

The analysis comprised data from 67 adults with LGS from the randomized controlled trial (RCT) portion and 41 who continued into the OLE. Coming into the RCT, 36% to 56% of fenfluramine-treated patients had global executive composite (GEC) T scores of at least 65 on the Behavior Rating Inventory of Executive Functioning-Adult (BRIEF-A) assessment.

Across the RCT and OLE, investigators looked at median changes in BRIEF-A T-scores from baseline for Behavioral Regulation Index (BRI), Metacognition Index (MI), and GEC. Here, results showed that treatment with fenfluramine led to numerical decreases from baseline to RCT end of study on MI (0.2 mg, 54%-33%; 0.7 mg, 67%-56%), and GEC (0.2 mg, 50%-33%; 0.7 mg, 56%-50%) while those in the placebo group showed numerical increases (MI, 44%-52%; GEC, 36%-52%).

Patients were set to receive 0.2 mg/kg/d of fenfluramine in the OLE, titrated up to 0.7 mg/kg/d after 1 month. Overall, nearly half of the patients (19 of 41) in the OLE received a mean daily dose (MDD) of less than 0.3 mg/kg/d. Within this group, investigators observed numerical decreases in the percentage of patients with T-scores of more than 65 for BRI (26%-11%) and GEC (47%-32%). Notably, there were still decreases in the percentage of patients with these scores who were on fenfluramine MDD of more than 0.5 mg/kg/d (GEC, 25%-0%).

In the analysis, researchers found that correlations between change in frequency of seizures associated with a fall and BRIEF-A Indexes/Composite were negligible to weak in the fenfluramine and placebo groups in the RCT (BRI, –0.232 to 0.113; MC, –0.129 to 0.178; GEC, –0.138 to 0.024). In addition, there was a weak correlation with any fenfluramine dose in the OLE (BRI, –0.206; MC, –0.206; GEC, –0.239). At OLE month 12, the change in number of seizures associated with a fall was –13.5 (–258.2 to 36.8) for fenfluramine doses less than 0.3 mg/kg/d, –35.2 (–1194.2 to –2.8) for doses between 0.3 and 0.5 mg/kg/d and –26.5 (–58.5 to –18.2) for doses greater than 0.5 mg/kg/d.

LGS is a developmental and epileptic encephalopathy characterized by tonic seizures, at least 1 additional seizure type, and developmental impairment. It typically begins in childhood and frequently persists into adulthood.⁴ Seizures often remain resistant despite available antiseizure medications, while cognitive, behavioral, communication, sleep, and mobility impairments contribute substantially to disease burden.

Fenfluramine was originally approved in 2020 and had its indication expanded in 2022 based on data from the aforementioned phase 3 study.⁵ Otherwise known as Study 1601, patients were initially started on 0.2 mg/kg/d of fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3-month intervals. In 2023, a published interim analysis showed that fenfluramine-treated patients with LGS experience sustained reductions in monthly drop seizure frequency (MDSF), with a particularly robust reduction in the frequency of generalized tonic-clonic seizures (GTCS).

In the published findings, the median percentage change in MDSF was –28.6% over the entire OLE (n = 241) and –50.5% at month 15 (n = 142; P <.0001). GTCS and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (P <.0001; n = 106) and 35.8% (P <.0001; n = 186), respectively. Notably, 37.6% (95% CI, 31.4%-44.1%) of investigators and 35.2% of caregivers (95% CI, 29.1%-41.8%) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement Scale.

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. Epilepsia Open publishes results of post hoc data analysis of FINTEPLA (fenfluramine) in patients with Lennox-Gastaut syndrome. News release. UCB. August 4, 2026. Accessed August 11, 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
3. Breuillard D, Knupp K, Strzelczyk A, et al. Association of fenfluramine treatment and everyday executive functioning in adult patients with Lennox-Gastaut syndrome. Presented at: 2025 AES Annual Meeting; Dec 5-9, 2025; Atlanta, GA. Abstract 2.430.
4. Specchio N, Wirrell EC, Scheffer IE, et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63(6):1398-1442.
5. Fintepla (fenfluramine) oral solution now FDA approved for treatment of seizures associated with Lennox-Gastaut syndrome (LGS). News release. UCB. March 28, 2022. Accessed August 11, 2026. https://finance.yahoo.com/news/fintepla-fenfluramine-oral-solution-now-050000058.html