Abstracts

Rationale: Dravet syndrome (DS) is a severe, drug-resistant epilepsy syndrome.  Fenfluramine (FFA) has been reported to have a long-term clinically meaningful anticonvulsive effect in patients with DS. Here we describe the follow-up results from a cohort of DS patients who were placed on FFA treatment during a prospective study which began in 2010. Methods: Patients from 6 mo to 50 yrs of age with a diagnosis of DS were eligible to enroll. Patients with cardiovascular disease, including drug-treated hypertension and cardiac valvulopathy, were excluded. Following a 3-month baseline period, fenfluramine was added to each patient’s current anti-epileptic drug regimen at a dose of 0.10 to 1.0 mg/kg/day (max 20mg/day).  The incidence of major motor seizures (tonic, clonic, tonic-clonic, atonic, and myoclonic seizures lasting >30 sec) in both the baseline and treatment periods was assessed via a seizure diary. During the first three months concomitant AED’s were kept stable, thereafter adjustments could be made if necessary. Efficacy and adverse events (AEs) were monitored at scheduled and unscheduled office visits. Results: Nine patients have enrolled (5 male, 4 female). Mean age at the start of FFA was 13.5 years (range, 1 to 29 years). All had a typical core DS fenotype with a confirmed de novo mutation in SCN1A. All patients were receiving at least 2 other antiepileptic drugs at study entry, including valproate (n=9), topiramate (n=8), ethyl loflazepate (n=4), clobazam (n=3), stiripentol (n=2), bromide (n=1) and levetiracetam (n=1). Three patients had a vagal nerve stimulator (VNS) with stable settings. The median starting FFA dose was 10 mg per day (range, 5 to 10 mg) or 0.23 mg/kg/day (range, 0.10 to 0.50 mg/kg/day). During the 3-months baseline observation prior to starting FFA, median frequency of major motor seizures seizures was 15/month (range 0.4 to 39.7). All patients demonstrated a decrease in the frequency of major motor seizures during FFA treatment. At the 3 months evaluation the median frequency of major motor seizures was 2.0/month representing a median decline of 84%. Over the entire observation period (median 22 months; range, 9 to 67 months) the median frequency of major motor seizures was 1.9/month representing a 76.5% reduction compared to the 3 month baseline period. Seven patients (78%) experienced a ≥50% reduction in major motor seizure frequency.  The most common adverse events were somnolence (n=5) and anorexia (n=4). No evidence of cardiac valvulopathy or pulmonary hypertension was observed. One patient had a subnormal systolic function (fractional shortening 26%  and ejection fraction 53 %) due to mild hypokinesia of  the interventricular septum without any clinical significance. Conclusions: The results of this prospective study suggest that FFA provides a significant improvement in seizure frequency while being generally well tolerated. The effectiveness and safety of low-dose FFA as add-on therapy for Dravet syndrome in this new prospective cohort supports previous findings Funding: This investigator initiated trial was supported by Zogenix.