Abstracts

Rationale: Dravet syndrome (DS), a drug-resistant, severe myoclonic epilepsy, typically presents in the first year of life. Between the ages of 1 to 5 years, seizure frequency and severity increase along with developmental delay, cognitive and behavioral problems. Fenfluramine (FFA) has been reported to provide antiepileptic activity in a retrospective chart review of 12 DS patients (original cohort, Ceulemans B. et al., Epilepsia 2012;53:1131-9). Here we describe the initial results from a new cohort of DS patients who were placed on FFA treatment during a prospective study that began in 2010 with initiation of a standardized protocol of assessments.Methods: Patients from 6 months to 50 years of age with a diagnosis of DS were eligible to enroll. Patients with cardiovascular disease, including drug-treated hypertension and cardiac valvulopathy, were excluded. At baseline, seizure frequency and type were monitored for 3 months using a diary before adding FFA to the current treatment regimen. Thereafter, efficacy and adverse events were monitored at scheduled and unscheduled office visits. FFA doses could be adjusted at the discretion of the treating physician up to a maximum of 20 mg/day.Results: Seven patients have enrolled (5 male, 2 female) to date. Mean age at the start of FFA was 12.2 years (range, 1 to 20 years). All had a confirmed mutation in SCN1A. All patients were receiving at least 2 other antiepileptic drugs at study entry, including valproate (n=7), topiramate (n=6), clobazam (n=3), stiripentol (n=2), ethyl loflazepate (n=2), bromide (n=1) and levetiracetam (n=1). The median starting FFA dose was 10 mg per day (range, 5 to 10 mg). During the 3-month baseline observation prior to starting FFA, the median frequency of tonic/clonic (TC) seizures was 3.0/month (range 0.4 to 39.7). All patients demonstrated a decrease in the frequency of TC seizures during FFA treatment. At the 6-month evaluation, the median frequency of TC seizures was 1.2/month, representing a decline of 73%. Over the entire observation period (median 0.9 year; range, 0.22 to 3.91 years) the median frequency of TC seizures was 0.9/month representing an 84% reduction compared to the 3-month baseline period (Figure). Most common treatment-related adverse events were mild to moderate somnolence (n=6) and anorexia (n=4). One patient, who was hospitalized 11 times for seizures during the pre-FFA period, experienced 4 separate episodes of status epilepticus with fever due to respiratory infection.Conclusions: The results of this prospective study suggest that FFA provides a significant improvement in seizure frequency while being generally well tolerated. These findings add to the effectiveness and tolerability demonstrated in the original cohort report. Brabant Pharma and Zogenix, Inc. funded the study and its analysis. Medical writing assistance was provided by PharmaWrite (Princeton, NJ) and was funded by Zogenix Inc.