Fenfluramine Safe and Effective in Lennox-Gastaut Syndrome Regardless of Concomitant Vagus Nerve Stimulation
In both the randomized controlled trial and open-label extension, a higher proportion of patients without VNS achieved at least 50% and 75% seizure reductions compared to those with concomitant VNS treatment.
A post-hoc analysis of the phase 3 1601 study (NCT03355209) and its open-label extension (OLE) revealed that fenfluramine (Fintepla; UCB) was effective and safe in patients with Lennox-Gastaut syndrome (LGS) irresponsive of concomitant use of vagus nerve stimulation (VNS). In fact, at times, patients on a combination of both fenfluramine and VNS performed worse on responder analyses and experienced fatigue more frequently, raising the need to further investigate the settings and duration of VNS therapy.1
In the original 14-week randomized controlled trial (RCT), patients were randomized to fenfluramine 0.2 mg/kg/day, fenfluramine 0.7 mg/kg/day (max 26 mg/day) or placebo. In the OLE, patients transitioned to fenfluramine 0.2 mg/kg/day for 1 month, followed by flexible titration, with no changes to VNS settings or concomitant antiseizure medications (ASMs) allowed during the RCT and first 6 months of the OLE.
Led by Lieven Lagae, MD, PhD, a professor of pediatric neurology at the University of Leuven, in Belgium, results showed that a combination of fenfluramine and VNS led to greater reductions in generalized tonic-clonic seizures (GTCS) than without VNS during the RCT; however, in the OLE, data showed a higher median reduction in GTCS when fenfluramine was given alone. In the RCT, investigators reported median reductions of –69.6% (0.2 mg/kg/day) and –50.1% (0.7 mg/kg/day) in GTCS in the combination group vs reductions of –57.0% and –41.2% for those without, respectively. In comparison, those on fenfluramine without VNS experienced median reductions of –56.3% in the OLE vs reductions of –37.9% for those with VNS.
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In the OLE, where patients were flexibly titrated treatment to effect and tolerability, 32.9% and 13.7% of fenfluramine-treated patients without VNS achieved at least 50% and 75% reduction in seizures associated with a fall, respectively, versus 27.5% and 7.5% of patients on concomitant treatment. In terms of safety, among the commonly reported treatment-emergent adverse events (TEAEs) observed in the RCT and OLE, fatigue was more prevalent among patients on both fenfluramine and VNS vs those without VNS (RCT: 17.1% vs 11.6%; OLE: 18.8% vs 11.2%).
Study 1601, the study that led to fenfluramine’s 2022 approval in LGS,
The percentage reduction in GTC frequency during the titration and maintenance period was 45.7% in the fenfluramine 0.7-mg/kg/day group (P <.001) and 58.2% in the 0.2-mg/kg/day group (P <.001) compared with an increase of 3.7% in the placebo group. In the fenfluramine 0.7- and 0.2-mg/kg/day groups, the estimated median difference in GTC seizure frequency was –50.3% (95% CI, –76.7 to –23.8; P = .001) and –60.4% (95% CI, –84.9 to –36.0; P <.001), respectively, compared with placebo.
Originally marked as a Schedule IV controlled substance,
REFERENCES
1. Lagae L, Knupp K, Sullivan J, et al. A post-hoc evaluation of fenfluramine with or without vagus nerve stimulation in Lennox-Gastaut syndrome clinical trials. Presented at: 2024 AES Annual Meeting; December 6-10; Los Angeles, CA. ABSTRACT 1.336
2. Knupp KG, Scheffer IE, Ceulemans B, et al. Efficacy and safety of fenfluramine for the treatmet of seizures associated with Lennox-Gastaut syndrome: a randomized clinical trial. JAMA Neurol. Published online May 2, 2022. doi:10.1001/jamaneurol.2022.0829
3. UCB announces Fintepla (fenfluramine) oral solution is now descheduled and is no longer listed as a controlled substance. News release. April 17, 2023. Accessed December 7, 2024. https://www.prnewswire.com/news-releases/ucb-announces-fintepla-fenfluramine-oral-solution-is-now-descheduled-and-is-no-longer-listed-as-a-controlled-substance-301798777.html
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