The addition of ZX008 to background stiripentol significantly reduced the number of convulsive seizures experienced by children and young adults with Dravet syndrome.
Linda Laux, MD
The addition of ZX008 (low-dose fenfluramine hydrochloride) to background stiripentol significantly reduced the number of convulsive seizures experienced by children and young adults with Dravet syndrome, according to topline findings from the phase III Study 1504 trial announced by Zogenix, the company developing the medication.
In the phase III study, ZX008 demonstrated a median 62.7% reduction in monthly convulsive seizures compared with 1.2% with placebo. The mean monthly reduction in compulsive seizures was 54.7% with ZX008 compared with placebo. Based on the findings from the study, regulatory submissions are planned in the United States and European Union before the end of the year, according to Zogenix.
“Patients with Dravet syndrome can often experience frequent, severe convulsive seizures that dramatically impact quality of life for them and their families,” Linda Laux, MD, associate professor, Pediatrics — Neurology, Ann & Robert H. Lurie Children’s Hospital of Chicago, said in a statement. “For patients who continue to have significant seizures and need new treatments to reduce seizure frequency and improve quality of life, ZX008 may be an exciting and important new treatment option.“
The phase III study randomized 87 patients at a median age of 9 years to receive ZX008 (n = 43) or placebo (n = 44) after 6 months of observation. All patients were receiving stable background treatment with stiripentol plus other antiepileptic drugs. ZX008 was given at 0.5 mg/kg per day (with a maximum dose of 20 mg). The dose was titrated for 3 weeks.
There were marked improvements in secondary endpoints with ZX008, including reductions in convulsive seizures of ≥50% and ≥75%. Overall, 53.5% of patients treated with ZX008 had a reduction in monthly compulsive seizures of ≥50% compared with just 6.8% with placebo. Additionally, 32.6% of patients had a ≥75% reduction with ZX008 compared with 2.3% with placebo. The long seizure-free interval was 22 days with ZX008 compared with 13 days for placebo.
The addition of ZX008 was well-tolerated, with no patients experiencing cardiac valvulopathy or pulmonary hypertension. The rate of serious adverse events (AEs) was similar in each arm, at 14% with ZX008 compared with 15.9% with placebo. Two patients discontinued treatment due to AEs in the ZX008 arm.
An ongoing open-label extension study remains ongoing, to further monitor cardiac safety. This trial is enrolling approximately 300 patients to receive treatment with ZX008.
“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,” principal investigator of Study 1504 Rima Nabbout, MD, PhD, Department of Pediatric Neurology, Reference Center for Rare Epilepsies, Necker Enfants Malades Hospital, said in a statement. “If approved, ZX008 has the potential to be a transformative treatment for Dravet syndrome, a rare and serious form of epilepsy with few available treatment options.”
ZX008 has received a prior breakthrough therapy designation from the FDA for the treatment of Dravet syndrome. The new drug application for the medication will be based on data from Study 1504 along with results from another phase III study, known as Study 1.
In this study, which was initially presented at the American Epilepsy Society Annual Meeting, there was a 63.9% reduction in mean monthly convulsive seizures with the 0.8 mg/kg per day dose of ZX008 compared with a 33.7% reduction with a lower 0.2 mg/kg per day dose. The median percent reduction in convulsive seizures was 72.4% at the largest dose, 37.6% with the 0.2 mg/kg dose, and 17.4% with placebo.
“Based on these highly compelling top-line results from both of our pivotal studies, we are now focused on submitting applications for regulatory approvals in the United States and Europe in the fourth quarter of 2018," Stephen J. Farr, PhD, president and CEO of Zogenix, said in a statement. "We are excited about ZX008’s potential to have a major impact in the treatment of patients with Dravet syndrome and their families.”