Garcia Pierce, J. and Mithal, D.S., 2020. Fenfluramine: New
Treatment for Seizures in Dravet Syndrome.. Pediatric Neurology Briefs, 34,
p.8. DOI: http://doi.org/10.15844/pedneurbriefs-34-8
Abstract
Investigators for the FAiRE DS Study Group assessed the
efficacy and safety of Fenfluramine for treating seizures in patients less than
18 y.o. with Dravet Syndrome in an international double-blind,
placebo-controlled clinical trial.
Investigators for the FAiRE DS Study Group assessed the
efficacy and safety of Fenfluramine for treating seizures in patients less than
18 y.o. with Dravet Syndrome in an international double-blind,
placebo-controlled clinical trial. A total of 119 patients (mean age 9.0 y, 54%
male) were enrolled in the study. Patients were on stable anti-epileptic drugs
with poorly controlled convulsive seizures, with an average monthly convulsive
seizure frequency (MCSF) of 40.3 in the prior 28 days. For a total of 14 weeks,
caregivers provided participants with either placebo, Fenfluramine 0.2mg/kg/day
or Fenfluramine 0.7mg/kg/day. Exclusion criteria included recent use of
Stiripentol, Cannabidiol or Serotonergic medications. Importantly, patients
were monitored with echocardiograms and electrocardiograms.
The study met the primary endpoint as patients saw a
significant estimated decline in the MCSF relative to placebo for both
Fenfluramine 0.7mg/kg/day (62.3% reduction, p>0.0001) and 0.2mg/kg/day
(32.4% reduction, p=0.0209). For the higher dose of Fenfluramine, a number of
secondary endpoints were met, including reduction in rescue medication use,
improvements in both caregiver and investigator assessments and improvement of
some behavioral measures. The high dose of Fenfluramine resulted in weight loss
for patients aged 13-18 years. Adverse side-effects where reported more in both
Fenfluramine groups (95%) compared to the placebo group (65%). The most common
side effects were decreased appetite, diarrhea, nasopharyngitis, lethargy, and
pyrexia. Fenfluramine was not associated with any cardiovascular complications.
COMMENTARY. Fenfluramine is an amphetamine derivative that
was found to have anti-epileptic effects since 1980s. The medication became
popular in the 1990s as an appetite suppressant but was removed from the market
due to cardiovascular complications at high doses. The mechanism by which
Fenfluramine treats seizures is believed to be through regulation of serotonin
signaling. Invertebrate animal models with SCN1A mutations demonstrate activity
at 5-HT1D and 5-HT2C receptors.
Dravet Syndrome is an epileptic encephalopathy with a
significant seizure burden, often refractory to anticonvulsant treatment. In
recent years, Stiripentol and Cannabidiol have been approved for the treatment
of seizures in Dravet Syndrome, both having encouraging clinical trial and
post-approval data. In this study 49% of patients were previously on
Stiripentol and 26% were previously on Cannabidiol, indicating an ongoing need
for additional treatment options.
The paper demonstrates that low dose Fenfluramine is a safe
and effective add-on medication for providers to consider to significantly
reduce seizure frequency in patients with Dravet Syndrome. Importantly, despite
extensive monitoring, no cardiovascular risk was associated with either dose of
Fenfluramine. Weight loss was a mild side effect that should be well-tolerated
if a patient experiences seizure reduction. Furthermore, a separate retrospective
analysis of 10 patients with Dravet Syndrome on long-term Fenfluramine (6-27
years) demonstrated better seizure control without any significant medication
side effects. The promising results in this study of Fenfluramine in Dravet
Syndrome raise the possibility of future studies using the medication to treat
additional forms of epilepsy.
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