A pilot, open‐label study of the effectiveness and tolerability of low‐dose <scp>ZX</scp>008 (fenfluramine <scp>HC</scp>l) in Lennox‐Gastaut syndrome

Lagae, Lieven; Schoonjans, An‐Sofie; Gammaitoni, Arnold R.; Galer, Bradley S.; Ceulemans, Berten

doi:10.1111/epi.14540

Cited by 62 publications

(66 citation statements)

References 26 publications

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“…Preliminary uncontrolled data suggest that ZX008 may also have antiseizure effects in patients with Lennox‐Gastaut syndrome. In an open‐label dose‐finding study in 13 patients with Lennox‐Gastaut syndrome, the frequency of major motor seizures (defined in this study as generalized tonic–clonic, tonic, atonic, and focal seizures with a motor component) declined from a median of 60 per month in the baseline period to 22 per month 12 weeks after adding ZX008 at doses from 0.2 to 0.8 mg/kg/d to their treatment regimens . Nine patients continued into an extension study and have been treated for 3‐15 additional months.…”

Section: Fenfluramine Hydrochloride (Zx008)mentioning

confidence: 93%

“…Nine patients continued into an extension study and have been treated for 3‐15 additional months. At their last study visit, monthly seizure frequency over a total of 8‐20 months had declined by 58% compared to baseline …”

Section: Fenfluramine Hydrochloride (Zx008)mentioning

confidence: 94%

“…In an open-label dose-finding study in 13 patients with Lennox-Gastaut syndrome, the frequency of major motor seizures (defined in this study as generalized tonic-clonic, tonic, atonic, and focal seizures with a motor component) declined from a median of 60 per month in the baseline period to 22 per month 12 weeks after adding ZX008 at doses from 0.2 to 0.8 mg/kg/d to their treatment regimens. 56 Nine patients continued into an extension study and have been treated for 3-15 additional months. At their last study visit, monthly seizure frequency over a total of 8-20 months had declined by 58% compared to baseline.…”

Section: Efficacy Datamentioning

confidence: 99%

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Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in more advanced clinical development

et al. 2018

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Summary The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13‐16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy. This progress report provides a summary of findings on investigational compounds for which data from both preclinical studies and studies in patients were presented. The compounds reviewed include anakinra, cannabidiol, cannabidivarin, fenfluramine, ganaxolone, medium‐chain fatty acids, padsevonil, and the valproic derivatives valnoctamide and sec‐butylpropylacetamide. On June 25, 2018, the US Food and Drug Administration approved a standardized formulation of cannabidiol oral solution for the treatment of seizures associated with Lennox‐Gastaut syndrome and Dravet syndrome in patients 2 years and older. The report shows that there continues to be a steady flow of potential antiepileptic drugs progressing to clinical development. Many of these compounds show innovative mechanisms of action, and some have already been tested in placebo‐controlled randomized controlled trials, with promising efficacy and safety results.

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Section: Fenfluramine Hydrochloride (Zx008)mentioning

confidence: 93%

Section: Fenfluramine Hydrochloride (Zx008)mentioning

confidence: 94%

Section: Efficacy Datamentioning

confidence: 99%

See 1 more Smart Citation

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in more advanced clinical development

et al. 2018

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“…21 The present findings that fenfluramine in DBA/1 mice is effective in preventing S-IRA susceptibility is likely due to the ability of this drug to enhance central serotonin release, 20,21 and is consistent with previous findings in this SUDEP model with fluoxetine, which enhances the action of serotonin by selectively blocking reuptake. 12 Fenfluramine also possesses potentially important differences from fluoxetine and other SSRIs, because it has been shown to be effectively anticonvulsant as an add-on agent in epilepsy syndromes, 22,23,33,45 with no evidence of adverse effects on seizure susceptibility reported anecdotally with SSRIs. 12 Fenfluramine also possesses potentially important differences from fluoxetine and other SSRIs, because it has been shown to be effectively anticonvulsant as an add-on agent in epilepsy syndromes, 22,23,33,45 with no evidence of adverse effects on seizure susceptibility reported anecdotally with SSRIs.…”

Section: Discussionmentioning

confidence: 99%

Fenfluramine, a serotonin‐releasing drug, prevents seizure‐induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP

Tupal

Faingold

2019

Epilepsia

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Summary Objective Prevention of sudden unexpected death in epilepsy (SUDEP) is a critical goal for epilepsy therapy. The DBA/1 mouse model of SUDEP exhibits an elevated susceptibility to seizure‐induced death in response to electroconvulsive shock, hyperthermia, convulsant drug, and acoustic stimulation. The serotonin hypothesis of SUDEP is based on findings that treatments which modify serotonergic function significantly alter susceptibility to seizure‐induced sudden death in several epilepsy models, including DBA/1 mice. Serotonergic abnormalities have also recently been observed in human SUDEP. Fenfluramine is a drug that enhances serotonin release in the brain. Recent studies have found that the addition of fenfluramine improved seizure control in patients with Dravet syndrome, which has a high incidence of SUDEP. Therefore, we investigated the effects of fenfluramine on seizures and seizure‐induced respiratory arrest (S‐IRA) in DBA/1 mice. Methods The dose and time course of the effects of fenfluramine (i.p.) on audiogenic seizures (Sz) induced by an electric bell in DBA/1 mice were determined. Videos of Sz‐induced behaviors were recorded for analysis. Statistical significance (P < 0.05) was evaluated using the chi‐square test. Results Sixteen hours after administration of 15 mg/kg of fenfluramine, a high incidence of selective block of S‐IRA susceptibility (P < 0.001) occurred in DBA/1 mice without blocking any convulsive behavior. Thirty minutes after 20‐40 mg/kg of fenfluramine, significant reductions of seizure incidence and severity, as well as S‐IRA susceptibility occurred, which were long‐lasting (≥48 hours). The median effective dose (ED50) of fenfluramine for significantly reducing Sz at 30 minutes was 21 mg/kg. Significance This study presents the first evidence for the effectiveness of fenfluramine in reducing seizure incidence, severity, and S‐IRA susceptibility in a mammalian SUDEP model. The ability of fenfluramine to block S‐IRA selectively suggests the potential usefulness of fenfluramine in prophylaxis of SUDEP. These results further confirm and extend the serotonin hypothesis of SUDEP.

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“…A recent phase II study in patients with Lennox‐Gastaut syndrome, a refractory epilepsy syndrome with heterogeneous etiology, showed a durable reduction in MConSF after fenfluramine. Patients receiving fenfluramine for up to 20 weeks achieved a median MConSF reduction of 53% ( N = 13); after 15 months in the long‐term extension, median MConSF reduction was 58% ( N = 9).…”

Section: Pharmacological Treatment Of Dsmentioning

confidence: 99%

An Old Drug for a New Indication: Repurposing Fenfluramine From an Anorexigen to an Antiepileptic Drug

Schoonjans

Ceulemans

2019

Clin Pharma and Therapeutics

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A pilot, open‐label study of the effectiveness and tolerability of low‐dose ZX008 (fenfluramine HCl) in Lennox‐Gastaut syndrome

Abstract: ZX008 provided clinically meaningful reduction (≥50%) in CS frequency in the majority of patients with LGS in this pilot study and was generally well tolerated. A phase 3, randomized, controlled study is ongoing.

Cited by 62 publications

References 26 publications

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in more advanced clinical development

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in more advanced clinical development

Fenfluramine, a serotonin‐releasing drug, prevents seizure‐induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP

An Old Drug for a New Indication: Repurposing Fenfluramine From an Anorexigen to an Antiepileptic Drug

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