HOUSTON – Low-dose fenfluramine was found to reduce seizures significantly among a small cohort with Dravet syndrome without the appearance of valvular abnormalities or pulmonary hypertension, according to a prospective study presented at a poster session of the annual meeting of the American Epilepsy Society.
Six of nine Dravet syndrome (DS) patients (66%) had at least a 50% reduction in major motor seizure frequency for at least 90% of the period during which they took fenfluramine. Five of the nine DS patients (56%) experienced a reduction in major motor seizure frequency of 75% or more for at least 60% of the median 1.9 years they were on fenfluramine.
According to lead author An-Sofie Schoonjans, MD, and her collaborators, the results suggest that “low-dose fenfluramine provides significant improvement in seizure frequency while being generally well tolerated in DS patients.”
The study criteria included patients aged 6 months to 50 years who had a DS diagnosis; enrollees ranged in age from 1.2 to 29.8 years when starting fenfluramine. Though criteria allowed enrollment of patients with and without a mutation in the SCN1A gene, all participants did have a de novo mutation of the SCN1A gene, according to Dr. Schoonjans of the department of pediatric neurology at Antwerp (Belgium) University Hospital and her colleagues. They wrote that mutations in the gene, which encodes the alpha subunit of type 1 voltage-gated sodium channels, are found in about 80% of DS patients.
During the 3-month run-in period that began the study, patients had a median seizure frequency of 15 seizures per month. Patients remained on their baseline antiepilepsy regimen during the run-in period and throughout the study, with fenfluramine used as add-on therapy. At baseline, all patients were taking valproic acid and at least one other antiepileptic medication; three patients were taking four medications and one was taking five medications. Three patients also had vagal nerve stimulators with stable settings.
Throughout the study period, patients or their caregivers kept a seizure diary, recording major motor seizures. Those keeping the diary were instructed to record all tonic-clonic, tonic, atonic, and myoclonic seizures lasting more than 30 seconds.
Three months after beginning treatment, the study population’s median seizure frequency fell to 2.0 per month (–84%). Frequency fell further during the first year, to 1.0 per month (–79%; a smaller percent reduction because data were not available for this time period for the patient with the highest seizure frequency). For the total treatment period, the median seizure frequency was 1.9 per month (–76%). The reduction in seizure frequency was statistically significant at all time points (P less than .05; compared with baseline).
Fenfluramine was generally well-tolerated. Five patients experienced somnolence, and four had loss of appetite.
To track cardiovascular safety, all patients had echocardiographs at baseline and every 3 months during the first year of treatment. Echocardiographs were performed every 6 months during the second year, and annually thereafter. One patient had systolic dysfunction characterized by a reduced ejection fraction (53%) and fractional shortening (26%), findings of “no clinical significance,” according to Dr. Schoonjans and her colleagues.
Fenfluramine was part of an oral weight loss drug combination, along with phentermine. The combo, known as “fen-phen,” was associated with increased rates of pulmonary hypertension and valve disease, particularly aortic valve thickening and regurgitation. It was withdrawn from the market in 1997. Though pulmonary hypertension would frequently resolve after discontinuing fen-phen, not all patients with valvulopathy experienced resolution, and case reports of patients with the aortic valve thickening typically seen with fenfluramine are still surfacing many years after the drug’s discontinuation (e.g., Tex Heart Inst J. 2011;38[5]:581-3).
Fenfluramine was typically given at doses up to 60 mg when used with phentermine for weight loss. The dosing for Dravet syndrome patients in this study was much lower and weight based, ranging from 0.1 to 1.0 mg/kg per day, with a maximum permitted dose of 20 mg/day.
Fenfluramine is a serotonin releaser, and serotonin is known to modulate the action of voltage-gated sodium channels. However, the exact mechanism by which the drug reduces seizure frequency is not known. Clinical trials are underway in the United States for both DS and Lennox Gastaut epilepsy, and fenfluramine has been granted orphan drug status in the United States and Europe, according to an announcement from Zogenix, the drug’s manufacturer.
The study was funded by Zogenix, which holds a Royal Decree to dispense the drug under the study conditions in Belgium, where the study took place. Zogenix also funded writing and editorial assistance for the poster presentation.
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