Weight loss drug promising treatment option for rare form of epilepsy in children

Fenfluramine, previously used as a weight loss agent, could be an important new treatment option for patients with Dravet syndrome.

USA: Treatment with fenfluramine in children having Dravet Syndrome led to a greater reduction in convulsive seizures compared to placebo treatment for 14 weeks, finds a recent study published in The Lancet. In phase III clinical trial, the drug when given at a low dose in addition to existing anti-epilepsy drugs appeared safe and effective for Dravet syndrome -- a rare, treatment-resistant epileptic disorder.

Fenfluramine is perhaps best known as having once made up the "Fen" part of the weight-loss drug Fen-Phen, with phentermine. Fen-phen was voluntarily withdrawn from the market by its manufacturer in 1997 after high rates of heart problems emerged among people given high doses of up to 220 mg per day.

Dravet syndrome is a severe form of epilepsy, affecting one in 15,700-22,000 babies born each year. It is a type of epilepsy with seizures that are often triggered by hot temperatures or fever. Dravet syndrome is responsible for about 10% of childhood-onset epilepsy cases, where patients have frequent, debilitating seizures, neurodevelopmental, motor and behavioral problems and high mortality due to sudden unexpected death in epilepsy (SUDEP). Compared with the general population of patients with epilepsy, Dravet syndrome patients have a substantially higher rate of SUDEP.

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Current therapies are inadequate for most patients, and approximately 45% of patients have more than three convulsive seizures per month despite multiple antiepileptic drugs.

Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study by Prof Lieven Lagae, University of Leuven, Leuven, Belgium, and colleagues was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome.

Two identical 14 week-long phase 3 RCTs were designed for the study -- one trial in the US and Canada and the other in western Europe and Australia. The results of the two trials were merged and analyzed together. They included a total of 119 participants with Dravet Syndrome aged 2-18 years. The participants had a high seizure burden, with an average of about 1.5 convulsion seizures per day (around 40 seizures within 28 days).

The patients were divided into three groups -- 1) receiving placebo (n=40); 2) a low dose of fenfluramine (0.2mg per kg per day) (n=39); and 3) a higher dose (0.7mg per kg per day) (n=40). The drug was given orally by parents and caregivers.

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Key findings of the study include:

• 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; fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo.


• The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhea, 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.


• Nine patients withdrew before the end of the trial.

"The frequent seizures suffered in Dravet syndrome impact on the lives of patients and their families. The patients in this study had a high baseline seizure burden with an average of approximately 40 seizures per month across all treatment groups. In our clinical trial, we saw impressive reductions in seizures in the patients who received fenfluramine compared with those on the placebo, and although further study will need to assess the long-term safety, I am optimistic about what we have seen so far, said Dr. J. Helen Cross, UCL Great Ormond Street NIHR BRC Institute of Child Health, UK,

"In Dravet syndrome, fenfluramine provided a 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," concluded the authors

The study, "Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial," is published in The Lancet.

DOI: https://doi.org/10.1016/S0140-6736(19)32500-0