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Published in: Current Treatment Options in Neurology 12/2022

24-09-2022 | Epilepsy | Epilepsy (E Waterhouse, Section Editor)

Fenfluramine for the Treatment of Dravet Syndrome and Lennox Gastaut Syndrome: A Review

Authors: Douglas R. Nordli III, MD, Fernando N. Galan, MD

Published in: Current Treatment Options in Neurology | Issue 12/2022

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Abstract

Purpose of Review

Treatment-resistant epilepsy comprises approximately 36.3% of neurology clinic-based populations in the USA. Despite new drug development over the past 50 years, the rates of drug-resistant epilepsy remain the same. The need for continued drug trials with novel mechanisms of action remains paramount in patients with drug-resistant epilepsy. In particular, patients with severe epilepsy syndromes such as Dravet syndrome (DS) and Lennox Gastaut syndrome (LGS) continue to be the most severely affected due to the increased rates of status epilepticus and sudden unexpected death (SUDEP).

Recent Findings

Fenfluramine has recently been FDA-approved for DS and LGS. There is substantial evidence highlighting the efficacy of fenfluramine in the treatment of seizures associated with DS and LGS. There are a growing number of studies investigating alternative uses of fenfluramine for treatment-resistant epilepsies.

Summary

The completed studies suggest that fenfluramine is both a safe and efficacious adjunctive therapy in the treatment of convulsive seizures and drop seizures associated with DS and LGS. Fenfluramine’s suggested mechanism of action and available human evidence likely support its efficacy as an add-on therapy for more seizure types and calls for further research to expand its clinical use.
Literature
1.
go back to reference Sultana B, et al. Incidence and prevalence of drug-resistant epilepsy: a systematic review and meta-analysis. Neurology. 2021;96(17):805–17.CrossRef Sultana B, et al. Incidence and prevalence of drug-resistant epilepsy: a systematic review and meta-analysis. Neurology. 2021;96(17):805–17.CrossRef
2.
go back to reference Cross JH, et al. Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome. Seizure. 2021;93:154–9.CrossRef Cross JH, et al. Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome. Seizure. 2021;93:154–9.CrossRef
4.
go back to reference Fuller RW, Snoddy HD, Robertson DW. Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats: uptake inhibition versus release. Pharmacol Biochem Behav. 1988;30(3):715–21.CrossRef Fuller RW, Snoddy HD, Robertson DW. Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats: uptake inhibition versus release. Pharmacol Biochem Behav. 1988;30(3):715–21.CrossRef
5.
go back to reference Zhang Y, et al. Pharmacological characterization of an antisense knockdown zebrafish model of Dravet syndrome: inhibition of epileptic seizures by the serotonin agonist fenfluramine. PLoS ONE. 2015;10(5):e0125898.CrossRef Zhang Y, et al. Pharmacological characterization of an antisense knockdown zebrafish model of Dravet syndrome: inhibition of epileptic seizures by the serotonin agonist fenfluramine. PLoS ONE. 2015;10(5):e0125898.CrossRef
6.
go back to reference Munro JF, Seaton DA, Duncan LJ. Treatment of refractory obesity with fenfluramine. BMJ. 1966;2(5514):624.CrossRef Munro JF, Seaton DA, Duncan LJ. Treatment of refractory obesity with fenfluramine. BMJ. 1966;2(5514):624.CrossRef
7.
go back to reference Casaer P, Boel M. Fenfluramine as a potential antiepileptic drug. Epilepsia J Int League Against Epilepsy. 2002;43(2):205. Casaer P, Boel M. Fenfluramine as a potential antiepileptic drug. Epilepsia J Int League Against Epilepsy. 2002;43(2):205.
8.
go back to reference Connolly HM, et al. Valvular heart disease associated with fenfluramine–phentermine. N Engl J Med. 1997;337(9):581–8.CrossRef Connolly HM, et al. Valvular heart disease associated with fenfluramine–phentermine. N Engl J Med. 1997;337(9):581–8.CrossRef
9.
go back to reference Aicardi J, Gastaut H. Treatment of self-induced photosensitive epilepsy with fenfluramine. N Engl J Med. 1985;313(22):1419.CrossRef Aicardi J, Gastaut H. Treatment of self-induced photosensitive epilepsy with fenfluramine. N Engl J Med. 1985;313(22):1419.CrossRef
10.
go back to reference Gastaut H, Zifkin B, Rufo M. Compulsive respiratory stereotypies in children with autistic features: polygraphic recording and treatment with fenfluramine. J Autism Dev Disord. 1987;17(3):391–406.CrossRef Gastaut H, Zifkin B, Rufo M. Compulsive respiratory stereotypies in children with autistic features: polygraphic recording and treatment with fenfluramine. J Autism Dev Disord. 1987;17(3):391–406.CrossRef
11.
go back to reference Ceulemans B, et al. Successful use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia. 2012;53(7):1131–9.CrossRef Ceulemans B, et al. Successful use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia. 2012;53(7):1131–9.CrossRef
12.
go back to reference Bonnycastle DD, Giarman NJ, Paasonen M. Anticonvulsant compounds and 5-hydroxy-tryptamine in rat brain. Br J Pharmacol Chemother. 1957;12(2):228–31.CrossRef Bonnycastle DD, Giarman NJ, Paasonen M. Anticonvulsant compounds and 5-hydroxy-tryptamine in rat brain. Br J Pharmacol Chemother. 1957;12(2):228–31.CrossRef
13.
go back to reference Jobe PC, Browning RA. The serotonergic and noradrenergic effects of antidepressant drugs are anticonvulsant, not proconvulsant. Epilepsy Behav. 2005;7(4):602–19.CrossRef Jobe PC, Browning RA. The serotonergic and noradrenergic effects of antidepressant drugs are anticonvulsant, not proconvulsant. Epilepsy Behav. 2005;7(4):602–19.CrossRef
14.
go back to reference Nabbout R, et al. Fenfluramine for treatment-resistant seizures in patients with Dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurol. 2020;77(3):300–8.CrossRef Nabbout R, et al. Fenfluramine for treatment-resistant seizures in patients with Dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurol. 2020;77(3):300–8.CrossRef
15.
go back to reference Sullivan J, et al. Fenfluramine responder analyses and numbers needed to treat: Translating epilepsy trial data into clinical practice. Eur J Paediatr Neurol. 2021;31:10–4.CrossRef Sullivan J, et al. Fenfluramine responder analyses and numbers needed to treat: Translating epilepsy trial data into clinical practice. Eur J Paediatr Neurol. 2021;31:10–4.CrossRef
16.
go back to reference Lagae L, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. The Lancet. 2019;394(10216):2243–54.CrossRef Lagae L, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. The Lancet. 2019;394(10216):2243–54.CrossRef
17.
go back to reference Knupp KG, et al. Efficacy and safety of fenfluramine for the treatment of seizures associated with Lennox-Gastaut syndrome: a randomized clinical trial. JAMA Neurol. 2022;79(6):554–64.CrossRef Knupp KG, et al. Efficacy and safety of fenfluramine for the treatment of seizures associated with Lennox-Gastaut syndrome: a randomized clinical trial. JAMA Neurol. 2022;79(6):554–64.CrossRef
18.
go back to reference Serial echocardiographic assessment of patients with Dravet syndrome treated with fenfluramine (Fintepla®) for up to 3 years: no incidence of valvular heart disease or pulmonary artery hypertension. Serial echocardiographic assessment of patients with Dravet syndrome treated with fenfluramine (Fintepla®) for up to 3 years: no incidence of valvular heart disease or pulmonary artery hypertension.
19.
go back to reference Lai WW, et al. Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: analysis of an ongoing long-term open-label safety extension study. Epilepsia. 2020;61(11):2386–95.CrossRef Lai WW, et al. Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: analysis of an ongoing long-term open-label safety extension study. Epilepsia. 2020;61(11):2386–95.CrossRef
20.
go back to reference Sullivan J, Scheffer IE, Lagae L, Nabbout R, Pringsheim M, Talwar D, Polster T, Galer B, Lock M, Agarwal A, Gammaitoni A, Morrison G, Farfel G. Fenfluramine HCl (Fintepla®) provides long-term clinically meaningful reduction in seizure frequency: Analysis of an ongoing open-label extension study. Epilepsia. 2020 Nov;61(11):2396–404. https://doi.org/10.1111/epi.16722. Epub 2020 Oct 19. PMID: 33078386; PMCID: PMC7756901. Sullivan J, Scheffer IE, Lagae L, Nabbout R, Pringsheim M, Talwar D, Polster T, Galer B, Lock M, Agarwal A, Gammaitoni A, Morrison G, Farfel G. Fenfluramine HCl (Fintepla®) provides long-term clinically meaningful reduction in seizure frequency: Analysis of an ongoing open-label extension study. Epilepsia. 2020 Nov;61(11):2396–404. https://​doi.​org/​10.​1111/​epi.​16722. Epub 2020 Oct 19. PMID: 33078386; PMCID: PMC7756901.
21.
go back to reference Specchio N, et al. Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a real-world study. Epilepsia. 2020;61(11):2405–14.CrossRef Specchio N, et al. Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a real-world study. Epilepsia. 2020;61(11):2405–14.CrossRef
22.
go back to reference Sullivan J, et al. Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: a time-to-event analysis. Epilepsia. 2022;63(1):130–8.CrossRef Sullivan J, et al. Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: a time-to-event analysis. Epilepsia. 2022;63(1):130–8.CrossRef
Metadata
Title
Fenfluramine for the Treatment of Dravet Syndrome and Lennox Gastaut Syndrome: A Review
Authors
Douglas R. Nordli III, MD
Fernando N. Galan, MD
Publication date
24-09-2022
Publisher
Springer US
Published in
Current Treatment Options in Neurology / Issue 12/2022
Print ISSN: 1092-8480
Electronic ISSN: 1534-3138
DOI
https://doi.org/10.1007/s11940-022-00741-4

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