Monday, December 23, 2019

Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome

Lagae L, Sullivan J, Knupp K, Laux L, Polster T, Nikanorova M, Devinsky O, Cross JH, Guerrini R, Talwar D, Miller I, Farfel G, Galer BS, Gammaitoni A, Mistry A, Morrison G, Lock M, Agarwal A, Lai WW, Ceulemans B; FAiRE DS Study Group. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019
Dec 13. pii: S0140-6736(19)32500-0. doi: 10.1016/S0140-6736(19)32500-0. [Epub ahead of print]


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 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.


Courtesy of:

Treatment with Fintepla (ZX008) can provide a clinically meaningful and profound reduction in the frequency of seizures in Dravet syndrome patients, according to data from two Phase 3 clinical trials.

The most common cause of mortality in Dravet patients is either sudden unexpected death in epilepsy (SUDEP) or status epilepticus (long epileptic episodes). Generalized tonic-clonic seizures (seizures that start in both sides of the brain) are a major risk factor for SUDEP.

Fintepla is a low-dose oral solution of fenfluramine hydrochloride, being developed by Zogenix to treat epileptic seizures linked to Dravet syndrome. Its anti-epileptic properties are associated with the stimulation of serotonin release in the brain.

Researchers assessed the impact of Fintepla in combination with other antiepileptic therapy regimens on generalized tonic-clonic seizures, and focal to bilateral tonic-clonic seizures (which start on one side of the brain and spread to both sides) in children and teenagers with Dravet syndrome.

Results were presented in the poster, “ZX008 Fenfluramine HCl Significantly Reduces Frequency of Generalized Tonic-Clonic Seizures in Dravet Syndrome: Pooled Analysis from Two Phase 3 Clinical Trials,” at the recent 48th Annual meeting of the Child Neurology Society (CNS), held in Charlotte, North Carolina.

Researchers performed a pooled analysis of results from two randomized and placebo-controlled Phase 3 clinical trials (NCT02682927 and NCT02826863), which enrolled 206 patients ages 2 to 18.

Patients not currently on stiripentol (Diacomit, an approved add-on therapy) is were randomized to either placebo or Fintepla at 0.2 or 0.7 mg/kg/day (maximum daily dose of 26 mg/day). Patients being treated with stiripentol were treated with Fintepla at 0.4 mg/kg/day (maximum daily dose of 17 mg/day).

Fintepla’s use resulted in clinically meaningful (defined as a greater than 50% reduction) and profound reductions in the frequency of both generalized tonic-clonic and focal-to-bilateral tonic-clonic seizures.

Specifically, the frequency of focal-to-bilateral tonic-clonic seizures was reduced by 97%, 33%, and 69% in patients given Fintepla at 0.7, 0.4, and 0.2 mg/kg/day, respectively, and fell by 39% in the placebo group. (Abstract of study is on page S59; values match more recent poster data.) 

The most common treatment-related side effects included decreased appetite, lack of energy, fatigue, drowsiness, and diarrhea. No cases of cardiac valvular disease or pulmonary arterial hypertension were seen.

“[Fintepla] may represent an important, effective new treatment option for patients with Dravet syndrome,” the researchers wrote.

After an initial refusal by the U.S. Food and Drug Administration (FDA) to review its application requesting Fintepla’s approval  — due to incomplete submission of early studies and an accuracy problem in one clinical data set —  Zogenix resubmitted its new drug application for Fintepla to the FDA in late September.

Courtesy of a patient’s father

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