An investigative oral medication called ZX008 was seen to effectively reduce the frequency of seizures in children and adolescents with Dravet syndrome, including those who had not responded to prior therapies, and may come to offer “a new treatment option.”
ZX008 is a low-dose formulation of fenfluramine being developed by Zogenix. The compound can stimulate the release and activity of several neuroactive signaling molecules, including serotonin, which is known to have an antiepileptic effect.
Data from two parallel Phase 3 clinical trials, referred to by Zogenix as “Study 1,” (NCT02682927, and NCT02826863), in Dravet patients up to age 18 demonstrate the potential of this investigative therapy.
Study 1 included 119 patients whose seizures were not controlled. They were randomized to receive either ZX008 at one of two doses — 0.2 or 0.8 mg/kg per day — or placebo for a total of 14 weeks.
Previously reported results showed that treatment with ZX008 at the higher dose significantly reduced the number of monthly convulsive seizures by 63.9% compared to placebo.
Researchers here conducted an additional analysis that focused on patients previously treated with Diacomit (stiripentol), the only adjunctive seizure treatment for Dravet patients and approved in Europe, Australia, Canada, and Japan. In the U.S., it can be made available on a compassionate use request.
The study, “ZX008 (Fenfluramine HCL Oral Solution) in Dravet Syndrome: Effect on Convulsive Seizure Frequency in Subjects Who Failed Treatment with Stiripentol Prior to Study 1,” presented by Elaine C. Wirrell, director of Pediatric Epilepsy at the Mayo Clinic, showed the results of this post-hoc analysis evaluating the effect of ZX008 in 58 patients enrolled in Study 1, ages 2 to 18, who had previously failed treatment with stiripentol.
Those given 0.8 mg/kg per day of ZX008 experienced a mean 60.8% reduction in monthly convulsive seizures compared to placebo-treated children. The longest median seizure-free interval reported in the high-dose group was 24.5 days and 18 days in the low-dose group, compared to a nine-day interval in the placebo group.
ZX008 at the high dose also benefited what might be considered quality of life, improvements reported by parents or caregivers of patients and their clinicians, when compared to reports from placebo-treated patients.
“ZX008 provided robust improvement in frequency of convulsive seizures in subjects who had previously used stiripentol, the only approved treatment for seizures in Dravet syndrome,” the researchers wrote. “ZX008 may represent an effective new treatment option for these patients with Dravet.”
In general, ZX008 showed a good safety profile, being well-tolerated by treated patients.
“It is highly encouraging to see that the efficacy and tolerability in this subgroup of patients who had previously failed treatment with stiripentol was comparable to the full Study 1 population,” Rima Nabbout, MD, and one of the poster’s authors, said in a press release. “As stiripentol is a commonly used antiepileptic drug, it is important to understand how tolerable and effective ZX008 is in this subgroup of patients.”
A second poster, “Effect of ZX008 (Fenfluramine HCl Oral Solution) on Total Seizures in Dravet Syndrome“, and presented by Joseph Sullivan, MD, director of the Pediatric Epilepsy Center at University California San Francisco, focused on the results of a prespecified secondary analysis evaluating ZX008 impact on total seizure frequency in all Study 1 participants.
At baseline or the study’s start, patients’ average monthly total seizure frequency ranged from 40.7 to 53.9 in both treatment and placebo groups. After the 14-week treatment period, that total frequency decreased by 13.1% in placebo patients, and in treated patients by 34.3% in the lower-dose group (0.2 mg/kg/day) and by70.1% in the higher dose (0.8 mg/kg/day) group.
“The efficacy and safety data generated from ZX008 in Study 1 continue to be extremely compelling,” said Bradley M. Galer, MD, Zogenix’s executive vice president and CMO. “All patients in our second Phase 3 study in Dravet syndrome, Study 1504, are taking stiripentol as part of their baseline standard of care, which will provide prospective data on the efficacy and safety of ZX008 in this patient population.
In this pivotal study, involving 100 children and teenagers with Dravet at sites across the U.S. and Europe, the safety and effectiveness of oral ZX008 as add-on to standard treatment plus Diacomit is being evaluated.
ZX008 has been designated a breakthrough therapy by the U.S. Food and Drug Administration (FDA), an orphan drug and was placed on a fast track development by both the FDA and the European Medicines Agency (EMA).