Abstracts

Rationale: Patients with a Dravet syndrome (DS), an epilepsy syndrome mainly associated with mutations in SCN1A, often present with refractory seizures. This seizure burden has a negative influence on the quality of life (QoL) of patients and their families. We previously reported a beneficial anti-convulsive effect of fenfluramine in patients with DS and present here an update of this ongoing study. Methods: Patients from 6 months to 50 years of age with a diagnosis of DS were eligible to enroll. 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 20 mg/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 3 months concomitant AEDs were kept stable; thereafter, adjustments could be made if necessary. Efficacy and adverse events (AEs) were monitored at scheduled and unscheduled office visits. Caregivers were asked to provide a global impression of change (CGIC) at the most recent study visit. Results: Eleven patients, all with a core DS phenotype and de novo mutation in SCN1A, have enrolled (6 male, 5 female). Median age at the start of fenfluramine was 11.9 years (range, 1 to 29 years). All patients were receiving at least 2 other antiepileptic drugs at study entry, including valproate (n=11), topiramate (n=10), ethyl loflazepate (n=4), clobazam (n=3), stiripentol (n=2), bromide (n=1), and levetiracetam (n=2). Three patients had a vagal nerve stimulator (VNS) with stable settings. The median starting fenfluramine dose was 5 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-month baseline observation, median frequency of major motor seizures was 4.2/month (range 0.4 to 39.7). All patients demonstrated a decrease in seizure frequency during fenfluramine treatment. At 3 months the median frequency of major motor seizures was 1.3/month, representing a median reduction of 86%; while over the entire observation period (median 30 months; range, 3 to 74 months) it was 0.8/month, representing a median reduction of 79% reduction compared to the 3-month baseline period (Figure). Ten patients (91%) experienced a =50% reduction in major motor seizure frequency and 7 patients (63%) experienced a =75% reduction. Eight caregivers (73%) rated the CGIC of their child as “much improved” or “very much improved.” The most common AEs were somnolence (n=6) and anorexia (n=5). No echocardiographic or clinical evidence of cardiac valvulopathy or pulmonary hypertension was observed. In one male patient a mild stable diminished left ventricular functioning was seen at 3 consecutive measurements. Conclusions: The results of this prospective open-label study suggest that fenfluramine provides a significant and long-term improvement in seizure frequency while being generally well tolerated. Additionally, most caregivers assessed a positive CGIC during treatment. Funding: This study is supported by Zogenix, Inc.