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Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7–72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2–52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. Zogenix.

Dravet syndrome (DS) is one of the most pharmacoresistant and devastating forms of childhood epilepsy syndromes. Distinct de novo mutations in the SCN1A gene are responsible for over 80% of DS cases. While DS is largely resistant to treatment with existing anti-epileptic drugs, promising results have been obtained in clinical trials with human patients treated with the serotonin agonist fenfluramine as an add-on therapeutic. We developed a zebrafish model of DS using morpholino antisense oligomers (MOs) targeting scn1Lab, the zebrafish ortholog of SCN1A. Zebrafish larvae with an antisense knockdown of scn1Lab (scn1Lab morphants) were characterized by automated behavioral tracking and high-resolution video imaging, in addition to measuring brain activity through local field potential recordings. Our findings reveal that scn1Lab morphants display hyperactivity, convulsive seizure-like behavior, loss of posture, repetitive jerking and a myoclonic seizure-like pattern. The occurrence of spontaneous seizures was confirmed by local field potential recordings of the forebrain, measuring epileptiform discharges. Furthermore, we show that these larvae are remarkably sensitive to hyperthermia, similar to what has been described for mouse models of DS, as well as for human DS patients. Pharmacological evaluation revealed that sodium valproate and fenfluramine significantly reduce epileptiform discharges in scn1Lab morphants. Our findings for this zebrafish model of DS are in accordance with clinical data for human DS patients. To our knowledge, this is the first study demonstrating effective seizure inhibition of fenfluramine in an animal model of Dravet syndrome. Moreover, these results provide a basis for identifying novel analogs with improved activity and significantly milder or no side effects.

The aim of this study was to investigate the comparative antiseizure activity of the l-enantiomers of d,l-fenfluramine and d,l-norfenfluramine and to evaluate the relationship between their concentration in plasma and brain and anticonvulsant activity. d,l-Fenfluramine, d,l-norfenfluramine and their individual enantiomers were evaluated in the mouse maximal electroshock seizure (MES) test. d,l-Fenfluramine, d,l-norfenfluramine and their individual l-enantiomers were also assessed in the DBA/2 mouse audiogenic seizure model. All compounds were administered intraperitoneally. Brain and plasma concentrations of the test compounds in DBA/2 mice were quantified and correlated with anticonvulsant activity. In the MES test, fenfluramine, norfenfluramine and their enantiomers showed comparable anticonvulsant activity, with ED[sub.50] values between 5.1 and 14.8 mg/kg. In the audiogenic seizure model, l-norfenfluramine was 9 times more potent than d,l-fenfluramine and 15 times more potent than l-fenfluramine based on ED[sub.50] (1.2 vs. 10.2 and 17.7 mg/kg, respectively). Brain concentrations of all compounds were about 20-fold higher than in plasma. Based on brain EC[sub.50] values, l-norfenfluramine was 7 times more potent than d,l-fenfluramine and 13 times more potent than l-fenfluramine (1940 vs. 13,200 and 25,400 ng/g, respectively). EC[sub.50] values for metabolically formed d,l-norfenfluramine and l-norfenfluramine were similar to brain EC[sub.50] values of the same compounds administered as such, suggesting that, in the audiogenic seizure model, the metabolites were responsible for the antiseizure activity of the parent compounds. Because of the evidence linking d-norfenfluramine to d,l-fenfluramine to cardiovascular and metabolic adverse effects, their l-enantiomers could potentially be safer follow-up compounds to d,l-fenfluramine. We found that, in the models tested, the activity of l-fenfluramine and l-norfenfluramine was comparable to that of the corresponding racemates. Based on the results in DBA/2 mice and other considerations, l-norfenfluramine appears to be a particularly attractive candidate for further evaluation as a novel, enantiomerically pure antiseizure medication.

Background Fenfluramine is an antiseizure medication approved by the Food and Drug Administration for the treatment of Dravet syndrome in patients older than 2 years. Fenfluramine is an amphetamine derivative. It cross‐reacts with amphetamines in urine drug screen immunoassays. Patient Presentation A 2‐year‐old patient with Dravet syndrome had a cardiorespiratory arrest and tested positive for amphetamines in a urine drug screen, raising concerns of child abuse. Liquid chromatography–mass spectrometry confirmed the presence of fenfluramine but did not detect amphetamines. Conclusion Fenfluramine can result in a false‐positive amphetamine urine drug screen at the recommended dose for Dravet syndrome. Awareness of this potential cross‐reactivity can prevent undue child protective services reports, especially in patients at high risk for sudden death.

Background Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed in recent years with the approval of new antiseizure medications (ASMs). Objective The aim of this study was to estimate the comparative efficacy and tolerability of the ASMs for the treatment of seizures associated with DS using a network meta-analysis (NMA). Methods Studies were identified by conducting a systematic search (week 4, January 2023) of the MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ) databases. Any randomized, controlled, double- or single-blinded, parallel-group study comparing at least one ASM therapy against placebo, another ASM, or a different dose of the same ASM in participants with a diagnosis of DS was identified. The efficacy outcomes were the proportions of participants with ≥ 50% (seizure response) and 100% reduction (seizure freedom) in baseline convulsive seizure frequency during the maintenance period. The tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and who experienced at least one adverse event (AE). Effect sizes were estimated by network meta-analyses within a frequentist framework. Results Eight placebo-controlled trials were included, and the active add-on treatments were stiripentol ( n  = 2), pharmaceutical-grade cannabidiol ( n  = 3), fenfluramine hydrochloride ( n  = 2), and soticlestat ( n  = 1). The studies recruited 680 participants, of whom 409 were randomized to active treatments (stiripentol = 33, pharmaceutical-grade cannabidiol = 228, fenfluramine hydrochloride = 122, and soticlestat = 26) and 271 to placebo. Pharmaceutical-grade cannabidiol was associated with a lower rate of seizure response than fenfluramine hydrochloride (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07–0.54), and stiripentol was associated with a higher seizure response rate than pharmaceutical-grade cannabidiol (OR 14.07, 95% CI 2.57–76.87). No statistically significant differences emerged across the different ASMs for the seizure freedom outcome. Stiripentol was associated with a lower probability of drug discontinuation for any reason than pharmaceutical-grade cannabidiol (OR 0.45, 95% CI 0.04–5.69), and pharmaceutical-grade cannabidiol was associated with a lower proportion of participants experiencing any AE than fenfluramine hydrochloride (OR 0.22, 95% CI 0.06–0.78). Stiripentol had a higher risk of AE occurrence than pharmaceutical-grade cannabidiol (OR 75.72, 95% CI 3.59–1598.58). The study found high-quality evidence of efficacy and tolerability of the four ASMs in the treatment of convulsive seizures in DS. Conclusions There exists first-class evidence that documents the efficacy and tolerability of stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat for the treatment of seizures associated with DS, and allows discussion about the expected outcomes regarding seizure frequency reduction and tolerability profiles.

Objective To assess the efficacy and tolerability of fenfluramine (FFA) with concomitant potassium bromide (BR) in patients with Dravet syndrome (DS). Methods This multicenter retrospective study, conducted within the German compassionate use program, analyzed BR doses and serum levels before and after FFA initiation, adverse events (AEs), seizure reduction, and symptoms changes using the Clinical Global Impression of Change (CGIC) scale. Timepoints were defined as T0 (baseline), T1 (FFA initiation), T2 and T3 (first and second BR level measurement after FFA initiation). Results Twenty‐two patients (median age 8.9 years, range 2.2–26.7) treated with BR were included. Median duration of BR–FFA combination therapy was 7 months (range 0–28). BR doses were reduced at least once in 11 patients (50%) as a precaution or because of increased serum levels. At T3, mean BR dose was significantly lower compared to T0 (1217 mg/day, SD = 699 vs. 1755 mg/day, SD = 752.2; p = 0.04), but BR levels showed no significant difference between T2 or T3 and baseline. In contrast, for patients with stable BR doses (n = 14), mean BR level significantly increased from baseline (1376 mg/L, SD = 345.7) to T2 (1762 mg/L, SD = 553.3; p = 0.04). AEs were reported in 15 patients (68.2%) during the combination therapy, with the most common being somnolence (59.1%) and loss of appetite (22.7%). In 40.9% either FFA or BR were discontinued due to sedation. The responder rate for seizure reduction was 68.4% at 3 months and 76.9% at 6 months. Significance BR levels increased significantly after FFA initiation when BR doses were not reduced, contributing to adverse events—primarily somnolence—and resulting in the discontinuation of BR or FFA in some patients. Close monitoring of BR levels is crucial to minimize the risk of adverse events. Plain language summary This study investigated the combination of fenfluramine (FFA) and potassium BR in treating Dravet syndrome. It was found that it is effective in reducing seizures, but BR levels often went up after starting FFA, which caused side effects like drowsiness in many patients. In some cases, these side effects were serious enough that physicians had to stop either BR or FFA. The study highlights the need for careful monitoring of BR levels when using this combination to avoid potential side effects by reducing the BR dose early if needed.

Fenfluramine (Fintepla ® ) is an oral anti-seizure medication (ASM) with a novel mechanism of action consisting of activity in the serotonergic system coupled with positive allosteric modulation effects at sigma-1 receptors. Originally approved for use at high doses as an appetite suppressant, it was subsequently withdrawn after being linked to valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), before being investigated for use at low doses as an adjunctive ASM in patients with developmental epileptic encephalopathies, including Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) who have pharmacoresistant seizures. In clinical trials, treatment with adjunctive fenfluramine markedly reduced convulsive seizure frequency in patients with DS that were sustained for up to 3 years, and reduced drop seizure frequency in patients with LGS that were sustained for up to 1 year. Notably, fenfluramine was also associated with clinically meaningful improvements in aspects of everyday executive functioning (EF) not entirely explainable by seizure reduction alone. Furthermore, it was generally well tolerated with, importantly, no reports of VHD or PAH. Thus, adjunctive fenfluramine is a novel and effective treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients. Plain Language Summary Emerging in infancy and childhood, respectively, Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are severe developmental and epileptic encephalopathies. They are characterized by seizures that are frequently ‘pharmacoresistant’ [i.e. cannot be controlled by ≥ 2 anti-seizure medications (ASMs)] and that, along with cognitive and behavioural comorbidities, can have a major impact on the quality of life of patients (and their caregivers/family members) as they grow. Fenfluramine (Fintepla ® ) is an oral ASM with a distinctive dual mechanism of action, that is used at low doses. In clinical trials in patients with DS or LGS, adding fenfluramine to the existing ASM regimen produced significant and sustained reductions in pharmacoresistant seizures and was associated with clinically meaningful improvements in aspects of everyday executive functioning (EF; i.e. the ability to regulate cognition, emotions and/or behaviour). Importantly, there was no evidence of the heart complications previously observed with the use of high doses of fenfluramine as an appetite suppressant. Adjunctive fenfluramine is an effective and generally well-tolerated treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients.

Epilepsy affects approximately 1% of the world population. Patients have recurrent seizures, increased physical and psychiatric comorbidities, and higher mortality rate than the general population. Over the last 40 years, research has resulted in 20 new antiseizure medications (ASMs) approved between 1990 and 2018. In spite of this, up to one-third of patients (~ 1 million patients in the USA) have drug-resistant epilepsy (DRE), with little change between 1982 and 2018, a period of intense new ASM development. A minority of patients with DRE may benefit from surgical treatment, but this specialized care remains challenging to scale. Therefore, the greatest hope for breakthroughs for patients with DRE is in pharmacologic therapies. Recently, several advances promise to change the outcomes for patients with DRE. Cenobamate, a drug with dual mechanisms of modulating sodium channel currents and GABA-A receptors, achieves 90–100% seizure reduction in 25–33% of patients with focal DRE, a response not observed with other ASMs. Fenfluramine, a serotonin-acting drug, dramatically reduces the frequency of convulsive seizures in Dravet syndrome, a devastating developmental epileptic encephalopathy with severe DRE. Both drugs reduce mortality. In addition, the possibility of DRE prevention was recently raised in patients with tuberous sclerosis complex, a relatively common genetic form of epilepsy. A paradigm shift is emerging in the treatment of epilepsy. Seizure freedom has become attainable in a significant proportion of patients with focal DRE, and dramatic seizure reduction has been achieved in a developmental encephalopathy. Coupled with a rich pipeline of new compounds under clinical development, the long sought-after breakthrough in the treatment of epilepsy may finally be in sight.

Background The head-twitch response (HTR) in mice is considered a behavioral model for hallucinogens and serotonin 5-HT 2A receptor function, as well as Tourette syndrome in humans. It is mediated by 5-HT 2A receptor agonists such as ( ±)− 2,5-dimethoxy-4-iodoamphetamine (DOI) in the prefrontal cortex (PFC). The 5-HT 2A antagonist EMD 281014, can prevent both DOI-induced HTR during ageing and c-fos expression in different regions of PFC. Moreover, the nonselective monoamine releaser methamphetamine (MA) suppressed DOI-induced HTR through ageing via concomitant activation of inhibitory 5-HT 1A receptors, but enhanced DOI-evoked c-fos expression. d -Fenfluramine is a selective 5-HT releaser and induces HTR in mice, whereas MA does not. Currently, we investigated whether EMD 281014 or MA would alter: (1) d -fenfluramine-induced HTR frequency in 20-, 30- and 60-day old mice, (2) d -fenfluramine-evoked c- fos expression in PFC, and (3) whether blockade of inhibitory serotonergic 5-HT 1A - or adrenergic ɑ 2 -receptors would prevent suppressive effect of MA on d -fenfluramine-induced HTR. Results EMD 281014 (0.001–0.05 mg/kg) or MA (0.1–5 mg/kg) blocked d -fenfluramine-induced HTR dose-dependently during ageing. The 5-HT 1A antagonist WAY 100635 countered the inhibitory effect of MA on d -fenfluramine-induced HTR in 30-day old mice, whereas the adrenergic ɑ 2 antagonist RS 79948 reversed MA’s inhibitory effect in both 20- and 30- day old mice. d -Fenfluramine significantly increased c- fos expressions in PFC regions. MA (1 mg/kg) pretreatment significantly increased d -fenfluramine-evoked c- fos expression in different regions of PFC. EMD 281014 (0.05 mg/kg) failed to prevent d -fenfluramine-induced c- fos expression, but significantly increased it in one PFC region (PrL at − 2.68 mm). Conclusion EMD 281014 suppressed d -fenfluramine-induced HTR but failed to prevent d -fenfluramine-evoked c- fos expression which suggest involvement of additional serotonergic receptors in the mediation of evoked c- fos . The suppressive effect of MA on d -fenfluramine-evoked HTR is due to well-recognized functional interactions between stimulatory 5-HT 2A - and the inhibitory 5-HT 1A - and ɑ 2 -receptors. MA-evoked increases in c- fos expression in PFC regions are due to the activation of diverse monoaminergic receptors through increased synaptic concentrations of 5-HT, NE and/or DA, which may also account for the additive effect of MA on d -fenfluramine-evoked changes in c- fos expression. Our findings suggest potential drug receptor functional interaction during development when used in combination.