Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real‐world study

Abstract

Objective: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS. Methods: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months. Results: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. Significance: In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.

Efficacy, tolerability, and retention of fenfluramine for the treatment of seizures in patients with Dravet syndrome: Compassionate use program in Germany

“…25 It was also a commonly observed AE in our study and the Italian study, but in only 22% and 13% of patients, respectively; only one patient discontinued due to this AE in our study and none in the Italian study. In addition, in agreement with other studies, 16,25 we also commonly observed somnolence, although it only resulted in one patient discontinuing FFA. There were no cases of sudden unexpected death in epilepsy (SUDEP) and no deaths during the FFA treatment period, although evaluating the effects of FFA on SUDEP and mortality requires a study with a larger population and a longer surveillance period.…”

“…It is also notable that during treatment with FFA in our study, 45% of patients were able to discontinue concomitant ASMs, and the dose was tapered in a further 23% of patients. Specchio et al 16 also reported reductions in the medication burden (discontinuations or dose reductions of concomitant ASMs) with FFA in 46% of patients, although the proportion of patients who discontinued an ASM was lower than in our study (14% vs. 45%). This may be due to the longer follow‐up in our study, allowing more time to assess whether the patient had achieved a sustained period of seizure control before discontinuing concomitant ASMs.…”

“…Although it is not surprising that there are some differences in the responder rates between studies, possibly due to differences in patient characteristics, prior and concomitant treatments, doses, and follow-up times, these real-world studies and RCTs have consistently demonstrated that FFA results in a reduction in seizures in a substantial proportion of patients with DS. Furthermore, the ultimate treatment goal of seizure freedom or near freedom from seizures has been observed in a notable proportion of patients in our study (29.5% with ≤1 seizure per month) and others, 6,7,16 with Nabbout et al 7 reporting a statistically significant difference in the proportion of patients having ≤1 convulsive seizure during the 14-week treatment period with FFA compared to placebo (Table S3). Of note, FFA has also shown efficacy in reducing seizures in other drugresistant epilepsy syndromes including Lennox-Gastaut syndrome and CDKL5 deficiency disorder.…”

“…In the pivotal RCTs, ≥50% responder rates for convulsive seizures of 38%-68% across different doses/regimens were reported, 6,7 with rates of 64.5% observed in the OLE extension (median duration of treatment = 631 days; Table S3). 8-10 Specchio et al, 16 reporting on the Italian EAP experience, demonstrated a ≥50% responder rate for convulsive seizures of 71.1%, higher than in our study and in the RCTs. Although it is not surprising that there are some differences in the responder rates between studies, possibly due to differences in patient characteristics, prior and concomitant treatments, doses, and follow-up times, these real-world studies and RCTs have consistently demonstrated that FFA results in a reduction in seizures in a substantial proportion of patients with DS.…”

A systematic review of adults with Dravet syndrome

“…Other fenfluramine trials also observed a significant reduction in MCSF in children and young adults. These studies showed a higher dose of fenfluramine extended the amount of days without a seizure, relative to a smaller dose [47][48][49][50]. Fenfluramine has just been approved by FDA for use in patients with DS.…”