Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox–Gastaut syndrome: Interim analysis of an open‐label extension study

Knupp, Kelly G.; Scheffer, Ingrid E.; Ceulemans, Berten; Sullivan, Joseph; Nickels, Katherine C.; Lagae, Lieven; Guerrini, Renzo; Zuberi, Sameer M.; Nabbout, Rima; Riney, Kate; Agarwal, Anupam; Lock, Michael; Dai, David; Farfel, Gail; Galer, Bradley S.; Gammaitoni, Arnold R.; Polega, Shikha; Davis, Ronald L.; Gil‐Nagel, Antonio

doi:10.1111/epi.17431

Cited by 19 publications

(11 citation statements)

References 36 publications

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“…As the duration of the trials was short, the long-term effectiveness and safety of FFA cannot be fully characterized yet. In this regard, FFA provided a sustained seizure frequency reduction and was generally well tolerated over an extended period in patients who completed the double-blind studies and entered the open-label extension phases [41,42]. Further, no patient developed valvular heart disease or pulmonary arterial hypertension in the longitudinal assessment up to 36 months [43,44], supporting the safe cardiovascular profile of FFA that emerged with ongoing echocardiographic examinations during long-term treatment for up to 30 years in Belgium [13].…”

Section: Strengths and Limitationsmentioning

confidence: 63%

Efficacy and Safety of Fenfluramine in Epilepsy: A Systematic Review and Meta-analysis

et al. 2023

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Introduction: Fenfluramine(FFA) is an amphetamine derivative that promotes the release and blocks the neuronal reuptake of serotonin. Initially introduced as an appetite suppressant, FFA also showed antiseizure properties. This systematic review aimed to assess the efficacy and safety of FFA for the treatment of seizures in patients with epilepsy. Methods: We systematically searched (in week 3 of June 2022) MEDLINE, the Cochrane Central Register of Controlled Trials, and the US National Institutes of Health Clinical Trials Registry. Randomized, double-or single-blinded, placebo-controlled studies of FFA in patients with epilepsy and uncontrolled seizures were identified. Efficacy outcomes included the proportions of patients with C 50% and 100% reductions in baseline seizure frequency during the treatment period. Tolerability outcomes

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Section: Strengths and Limitationsmentioning

confidence: 63%

Efficacy and Safety of Fenfluramine in Epilepsy: A Systematic Review and Meta-analysis

et al. 2023

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“…For example, the incidence rate of clinically symptomatic valvulopathy is 7.1 per 10,000 individuals with less than 4 months of exposure, whereas it increases to 35 per 10,000 individuals with more than 4 months of exposure. 88,89 In the context of evaluating FFA for the treatment of Dravet syndrome and LGS, comprehensive monitoring programs with color Doppler echocardiographic examinations (performed at baseline, after ≈ 6-8 weeks of treatment and at study end in the core studies; 49,68 and at study entry, after 4-6 weeks of treatment, and then at 3-month intervals in the open label extension studies) 75,86,90,91 were implemented in all randomized controlled trials. These monitoring programs were designed to prospectively assess cardiac valve function and identify any signs of pulmonary arterial hypertension.…”

Section: Safety Of Fenfluraminementioning

confidence: 99%

“…FFA was generally well tolerated as a low-dose adjunctive treatment for seizures in patients with Dravet syndrome or LGS, both in the short term (14–15 weeks) 49 , 68 , 72 and in the longer term (up to 3.5 years). 75 , 86 Common adverse effects were decreased appetite, diarrhea, pyrexia, nasopharyngitis, lethargy, and drowsiness. Cardiovascular safety is an important endpoint when evaluating patients treated with FFA.…”

Section: Safety Of Fenfluraminementioning

confidence: 99%

Reintroducing Fenfluramine as a Treatment for Seizures: Current Knowledge, Recommendations and Gaps in Understanding

Dini,

Di Cara,

Ferrara

et al. 2023

NDT

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Despite the introduction of new anti-seizure medications in recent years, approximately one-third of the epileptic population continues to experience seizures. Recently, the anti-obesity medication fenfluramine (FFA) has been successfully repurposed, and it has received approval from various regulatory agencies for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome. The potential antiseizure effects of FFA were initially observed in patients with photosensitive epilepsy in the 1980s but it was not rigorously explored as a treatment option until 30 years later. This narrative review aims to provide an overview of the historical progression of FFA's use, starting from initial clinical observations to preclinical studies and, ultimately, successful clinical trials in the field of epilepsy.

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“…87 In an interim analysis of the open-label extension to this trial (median treatment duration, 364 days), patients continued to experience sustained reductions in drop seizure frequency and fenfluramine was generally well tolerated. 88 There were no reported cases of valvular heart disease or pulmonary arterial hypertension in the initial trial or open-label extension study. 87,88 Stiripentol Stiripentol (4,4-dimethyl-1-[3,4-[methylenedioxy]phenyl]-1-penten-3-ol) is an aromatic allylic alcohol that is structurally unrelated to other ASMs.…”

Section: Therapeutic Advances In Neurological Disordersmentioning

confidence: 96%

“…88 There were no reported cases of valvular heart disease or pulmonary arterial hypertension in the initial trial or open-label extension study. 87,88 Stiripentol Stiripentol (4,4-dimethyl-1-[3,4-[methylenedioxy]phenyl]-1-penten-3-ol) is an aromatic allylic alcohol that is structurally unrelated to other ASMs. 89 It was the first ASM to be granted orphan drug status by the European Medicines Agency in 2000 and was subsequently registered in Europe in 2007 as an orphan drug for the treatment of Dravet syndrome, as adjunctive therapy with valproate and clobazam.…”

Section: Therapeutic Advances In Neurological Disordersmentioning

confidence: 96%

Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies

Sills

2023

Ther Adv Neurol Disord

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Developmental and epileptic encephalopathies (DEEs) are rare neurodevelopmental disorders characterised by early-onset and often intractable seizures and developmental delay/regression, and include Dravet syndrome and Lennox–Gastaut syndrome (LGS). Rufinamide, fenfluramine, stiripentol, cannabidiol and ganaxolone are antiseizure medications (ASMs) with diverse mechanisms of action that have been approved for treating specific DEEs. Rufinamide is thought to suppress neuronal hyperexcitability by preventing the functional recycling of voltage-gated sodium channels from the inactivated to resting state. It is licensed for adjunctive treatment of seizures associated with LGS. Fenfluramine increases extracellular serotonin levels and may reduce seizures via activation of specific serotonin receptors and positive modulation of the sigma-1 receptor. Fenfluramine is licensed for adjunctive treatment of seizures associated with Dravet syndrome and LGS. Stiripentol is a positive allosteric modulator of type-A gamma-aminobutyric acid (GABAA) receptors. As a broad-spectrum inhibitor of cytochrome P450 enzymes, its antiseizure effects may additionally arise through pharmacokinetic interactions with co-administered ASMs. Stiripentol is licensed for treating seizures associated with Dravet syndrome in patients taking clobazam and/or valproate. The mechanism(s) of action of cannabidiol remains largely unclear although multiple targets have been proposed, including transient receptor potential vanilloid 1, G protein-coupled receptor 55 and equilibrative nucleoside transporter 1. Cannabidiol is licensed as adjunctive treatment in conjunction with clobazam for seizures associated with Dravet syndrome and LGS, and as adjunctive treatment of seizures associated with tuberous sclerosis complex. Like stiripentol, ganaxolone is a positive allosteric modulator at GABAA receptors. It has recently been licensed in the USA for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder. Greater understanding of the causes of DEEs has driven research into the potential use of other novel and repurposed agents. Putative ASMs currently in clinical development for use in DEEs include soticlestat, carisbamate, verapamil, radiprodil, clemizole and lorcaserin.

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Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox–Gastaut syndrome: Interim analysis of an open‐label extension study

Cited by 19 publications

References 36 publications

Efficacy and Safety of Fenfluramine in Epilepsy: A Systematic Review and Meta-analysis

Efficacy and Safety of Fenfluramine in Epilepsy: A Systematic Review and Meta-analysis

Reintroducing Fenfluramine as a Treatment for Seizures: Current Knowledge, Recommendations and Gaps in Understanding

Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies

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