Fenfluramine Treatment Leads to Long-Term Improved Everyday Executive Functioning in Lennox-Gastaut Syndrome

A post-hoc analysis from a phase 3 study and its open-label extension (NCT03355209) further confirmed the benefits of fenfluramine (Fintepla; UCB), an FDA-approved antiseizure medication, and its impact on everyday executive functioning (EEF) in adults with Lennox-Gastaut syndrome (LGS). 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.

Presented at the 2025 American Epilepsy Society (AES) Annual Meeting, held December 5-9 in Atlanta, Georgia, 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%-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 (EOS) 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%).

Led by a group of epilepsy experts, including Kelly Knupp, MD, MSCS, FAES, associate professor at Children’s Hospital Colorado, 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%).

READ MORE: Claims Study Highlights Persistence and Reasons for Fenfluramine Use in Lennox-Gastaut Syndrome

In the analysis, Knupp et al 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.

Fenfluramine was originally approved in 2020 and later had its indication expanded in 2022 based on data from the aforementioned phase 3 study.² 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 drop seizure frequency (MDSF), with a particular 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.³

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REFERENCES
1. 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; Abstract 2.430
2. FINTEPLA® (fenfluramine) Oral Solution Now FDA Approved for Treatment of Seizures Associated with Lennox-Gastaut Syndrome (LGS). News release. UCB. March 28, 2022. Accessed January 7, 2025. https://finance.yahoo.com/news/fintepla-fenfluramine-oral-solution-now-050000058.html
3. Knupp KG, Scheffer IE, Ceulemans B, et al. Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: interim analysis of an open-label extension study. Epilepsia. Published online October 5, 2022. doi:10.1111/epi.17431