The US Food and Drug Administration approved fenfluramine on June 25 to treat seizures in patients with Dravet syndrome who were at least two years of age.
The drug, which was used for weight loss and withdrawn from the market in 1992 due to safety concerns about heart valve complications, was found safe and effective for reducing seizures in children in two double-blind, randomized placebo-controlled phase 3 trials.
The approval was based on pivotal data reported in two studies, published in December 2019, in JAMA Neurology and The Lancet.
Both studies found that fenfluramine significantly lowered the frequency of convulsive seizures each month in patients whose seizures were not managed by at least one antiepileptic drug when combined with existing therapy compared with placebo.
Study Design, Results
In the JAMA Neurology study, Rima Nabbout, MD, PhD, of Paris Descartes University in France, and colleagues, wanted to determine if fenfluramine lowered monthly convulsive seizures compared with placebo in Dravet patients who were being treated with stiripentol-inclusive therapies.
The study included 87 patients with Dravet syndrome, ages 2 to 18 years. Those who took oral fenfluramine in addition to other antiepileptic drugs—valproate or clobazam— were 54 percent less likely to experience a seizure compared with those on placebo. About 54 percent of patients on fenfluramine had a 50 percent or greater reduction in the average monthly convulsive seizure frequency compared with 5 percent on placebo.
Diarrhea, pyrexia, fatigue, and decreased appetite were common adverse events. None of the participants developed pulmonary hypertension of valvular heart disease.
Adjunctive fenfluramine was both an effective and safe form of treatment for Dravet syndrome patients with uncontrollable seizures despite a treatment course involving stiripentol, the researchers concluded.
The Lancet Neurology study by Lieven Lagae, MD, of University of Leuven in Belgium, randomized 119 patients to fenfluramine 0.7 mg/kg per day, fenfluramine 0.2 mg/kg per day, or placebo.
The investigators reported a 32.4 percent reduction in average convulsive seizure frequency each month compared with placebo (p=0·0209) for patients receiving 0.2 mg/kg per day of fenfluramine and a 62.3 percent reduction for those receiving 0.7 mg/kg per day compared with placebo (p<0·0001).
The median reduction in seizure frequency was 74.9 percent, 42.3 percent, and 19.2 percent in the in the 0.7 mg/kg, 0.2 mg/kg, and placebo cohorts respectively, the investigators found.
Diarrhea, lethargy, fatigue, decreased weight and somnolence were the most common adverse events, they added.
Fenfluramine will be available to certified prescribers in the US in July.
"Having a new FDA-approved treatment option is so important because it improves our ability to optimize each patient's treatment," Mary Anne Meskis, executive director of the Dravet Syndrome Foundation, said in the US FDA announcement about the approval.
Link Up for More Information:
Nabbout R, Mistry A, Zuberi S, et al; Fenfluramine for treatment-resistant seizures in patients with dravet syndrome receiving stiripentol-inclusive regimens a randomized clinical trial. JAMA Neurol 2019; Epub 2019 December 2.
Lagae L, Sullivan J, Knupp K, et al; Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet 2019; Epub 2019 December 21.