WASHINGTON, DC—Among patients with Dravet syndrome, adjunctive treatment with fenfluramine hydrochloride oral solution significantly reduces convulsive seizure frequency, compared with placebo, according to data presented at the 71st Annual Meeting of the American Epilepsy Society. The treatment is generally well tolerated at doses of 30 mg/day or less, and no clinical or echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed in a phase III trial, investigators said.
Fenfluramine has been used at higher doses for weight loss, but the drug was withdrawn from US and European markets because it was associated with cardiac valvulopathy and pulmonary hypertension. Investigators in Belgium, however, continued exploratory studies of low-dose fenfluramine for refractory pediatric epilepsy. The studies suggested that fenfluramine reduced seizure frequency. Zogenix, based in Emeryville, California, is developing the drug, known as ZX008.
No FDA-approved treatments for seizures associated with Dravet syndrome exist, and 45% of patients with Dravet syndrome have four or more tonic-clonic seizures per month despite polytherapy with antiepileptic drugs (AEDs), said the investigators.
A Placebo-Controlled Trial
Lieven Lagae, MD, PhD, Professor at the University of Leuven in Belgium and Head of the Pediatric Neurology Department and Director of the Childhood Epilepsy Program at the University of Leuven Hospitals, and colleagues conducted a phase III, randomized, placebo-controlled, double-blind, 14-week, fixed-dose clinical trial at sites in the United States, Canada, Europe, and Australia.
The researchers included patients with Dravet syndrome ages 2 to 18 whose seizures were not completely controlled by their current AED regimen and whose medications and interventions (eg, ketogenic diet and vagal nerve stimulation) had been stable for at least four weeks before screening. The researchers excluded patients with a history of cardiovascular or cerebrovascular disease, concomitant serotonergic or cannabinoid treatment, treatment with stiripentol in the 21 days before screening, or any diagnosis that might alter the risk–benefit ratio or impede participation in the trial.
Patients underwent six weeks of baseline observation before they were randomized 1:1:1 to receive ZX008 (0.8 mg/kg/day), ZX008 (0.2 mg/kg/day), or placebo. The treatment period included a two-week titration period followed by a 12-week maintenance period. The maximum daily dose was 30 mg. The primary efficacy end point was change in mean convulsive seizure frequency from the baseline period to the 14-week treatment period between ZX008 (0.8 mg/kg/day) and placebo.
Frequency of Seizures
The study included 119 patients. Patients had a mean age of 9, and about 54% were male. Average baseline convulsive seizure frequency was about 42 seizures per 28 days.
Patients who received ZX008 (0.8 mg/kg/day) had a 63.9% reduction in mean monthly convulsive seizures, compared with placebo. The median percent reduction in monthly convulsive seizure frequency was 72.4% among patients who received ZX008 (0.8 mg/kg/day), compared with 17.4% among patients who received placebo.
Significantly more patients who received either dose of ZX008 had at least a 25%, 50%, or 75% reduction in convulsive seizures during treatment, compared with patients who received placebo. The median longest seizure-free interval was significantly longer in patients treated with ZX008 (0.8 mg/kg/day) or ZX008 (0.2 mg/kg/day), compared with patients who received placebo (20.5 days, 14 days, and nine days, respectively).
Noncardiovascular treatment-emergent adverse events included diarrhea, fatigue, lethargy, and decreased weight and appetite. “No cases of FDA-defined cardiac valvulopathy were observed during the trial,” the researchers said. “No echocardiographic findings or clinical symptoms suggesting pulmonary hypertension were noted.”
Caregivers and clinicians rated a greater proportion of patients who received ZX008 to be very much or much improved following treatment, compared with patients who received placebo. Results from another phase III trial are expected in 2018.
“Patients treated with ZX008 achieved a clinically meaningful reduction in seizure frequency,” said Dr. Lagae. “If approved, ZX008 could play an important role in changing the treatment paradigm for patients and their families whose lives have been greatly impacted by the lack of effective seizure control provided by current treatment options.”