Low-Dose Fenfluramine Performs in Dravet Syndrome in Second Phase 3 Clinical Trial

Fenfluramine, a drug that was previously sold as an appetite suppressant before it was withdrawn from the market in 1997 over concerns about its link to heart valve problems, may have a new application; low doses of fenfluramine hydrochloride have now proven successful in treating Dravet syndrome (DS), a particularly severe form of epilepsy.

DS, a severe, infantile-onset, highly treatment-resistant epileptic encephalopathy, is associated with an elevated risk of premature death and has few treatments available.

Zogenix, Inc., a pharmaceutical company developing a 0.5 mg/kg/day dose of fenfluramine under the name ZX008, this month revealed positive top-line results from its second phase 3 study of the investigational treatment for children and adults with DS. Like the first phase 3 trial, this study met its primary endpoint—demonstrating superiority to placebo—and both key secondary endpoints.

According to Zogenix, patients who took ZX008 had a 54.7% greater reduction in mean monthly convulsive seizures versus those who received placebo (P =.001), and the median reduction in monthly convulsive seizure frequency was 62.7% for those receiving the study drug versus 1.2% in those receiving the placebo. Patients receiving the study drug also showed improvements in the key secondary measures of clinically meaningful reductions (50% or more) in seizure frequency and longest seizure-free intervals.

Notably, the incidence of adverse events (AEs) was similar between the drug and placebo arms, and prospective cardiac safety monitoring throughout the study did not identify evidence of cardiac AEs in the patients.

These findings confirm those of the first phase 3 study, results of which were presented in 2017 at the American Epilepsy Society’s Annual Meeting; in the first study of 119 patients, the group who received ZX008 also experienced statistically significant, clinically meaningful reductions in seizure frequency compared with the placebo group, and no clinical or echocardiographic evidence of cardiac valvulopathy or pulmonary hypertension were observed.

“These impressive study results show the significant impact the addition of ZX008 made in reducing the burden of convulsive seizures for patients who are not adequately controlled using stiripentol, the standard of care for the treatment of Dravet syndrome in Europe,” said Professor Rima Nabbout, MD, PhD, principal investigator of the study, in a statement. “If approved, ZX008 has the potential to be a transformative treatment for [DS.]”

Zogenics reports that it is now preparing its regulatory applications for submission to US and European regulators by the end of the year.