Zogenix, Inc., a pharmaceutical company developing therapies for the treatment of rare central nervous system (CNS) disorders, today reported positive top-line results from its first Phase 3 trial (Study 1) for its investigational drug, ZX008 (low-dose fenfluramine hydrochloride), for the treatment of Dravet syndrome. The trial met its primary objective of demonstrating that ZX008, at a dose of 0.8 mg/kg/day, is superior to placebo as adjunctive therapy in the treatment of Dravet syndrome in children and young adults based on change in the frequency of convulsive seizures between the 6-week baseline observation period and the 14-week treatment period (p<0.001). ZX008 0.8 mg/kg/day also demonstrated statistically significant improvements versus placebo in all key secondary measures, including the proportion of patients with clinically meaningful reductions in seizure frequency and longest seizure-free interval. The same analyses comparing a 0.2 mg/kg/day ZX008 dose versus placebo also demonstrated statistically significant improvement compared with placebo.
“Dravet syndrome is a rare, but catastrophic form of epilepsy that can be devastating for patients and their families,” said Joseph Sullivan M.D., director of the Pediatric Epilepsy Center in UCSF Benioff Children’s Hospital San Francisco, and Principal Investigator of Study 1 in the U.S. “These results are truly exciting and demonstrate, in a large multicenter controlled trial, the impressive efficacy of low-dose fenfluramine for patients with Dravet syndrome. If approved, ZX008 could play an important role in treating this devastating condition.”
The randomized, double blind, placebo controlled, Phase 3 study enrolled 119 patients across sites in the United States, Canada, Europe, and Australia. The median age of patients was 8 years (range, 2-18 years). Following a six-week baseline observation period, patients were randomized to one of three treatment groups: ZX008 0.8 mg/kg/day (30 mg maximum daily dose; n=40), ZX008 0.2 mg/kg/day (n=39) and placebo (n=40) in which ZX008 or placebo was added to current regimens of antiepileptic drugs. Patients were titrated to their target dose over two weeks and then remained at that fixed dose for 12 weeks. The mean baseline convulsive seizure frequency across the study groups was approximately 40 seizures per month.
The primary efficacy measure was a comparison of the change in mean monthly convulsive seizure frequency between ZX008 0.8 mg/kg/day and placebo during the 14-week treatment period compared with the 6-week baseline observation period. Patients taking ZX008 0.8 mg/kg/day achieved a 63.9% reduction in mean monthly convulsive seizures compared to placebo (p<0.001). The median percent reduction in monthly convulsive seizure frequency was 72.4% among ZX008 0.8 mg/kg/day patients compared to 17.4% in placebo patients.
A key secondary endpoint was the same analysis for a comparison of ZX008 0.2 mg/kg/day and placebo. Patients taking ZX008 0.2 mg/kg/day achieved a reduction in mean monthly convulsive seizures of 33.7% compared to placebo (p=0.019). Collectively, these top-line data suggest a dose-response relationship for ZX008 in the adjunctive treatment of convulsive seizures in Dravet syndrome.
Additional key secondary objectives of the study were to compare 0.8 mg/kg/day and 0.2 mg/kg/day ZX008 (independently) with placebo in terms of (1) the proportion of patients who achieved ≥50% reductions in monthly convulsive seizures and (2) the median of the longest convulsive seizure-free interval. These results are shown in the following table. The proportion of patients who achieved ≥75% seizure reductions, a secondary efficacy measure, is also presented.
ZX008 was generally well-tolerated in this study with the adverse events consistent with the known safety profile of fenfluramine. The incidence of treatment emergent adverse events was higher in the treatment groups as compared to the placebo group, with 95% (n=38) of patients in the 0.8mg/kg/day group and 94.9% (n=37) of patients in the 0.2 mg/kg/day group experiencing at least one treatment emergent adverse event compared to 65.0% (n=26) of patients in the placebo group. The incidence of serious adverse events was similar in all three groups with 12.5% (n=5) of patients in the 0.8 mg/kg/day group and 10.3% (n=4) of patients in the 0.2 mg/kg/day group experiencing at least one treatment emergent serious adverse event compared to 10.0% (n=4) of patients in the placebo group. Five patients in the 0.8 mg/kg/day group had an adverse event leading to study discontinuation compared to none in the other treatment groups. Prospective cardiac safety monitoring throughout the study demonstrated no clinical or echocardiographic evidence of cardiac valvulopathy or pulmonary hypertension.
“On behalf of everyone at Zogenix, I would like to extend my sincere appreciation to the patients, families and investigators involved in this study. We are extremely pleased with the top-line efficacy and safety results from Study 1 which reinforce the potential of ZX008 to be an important new treatment for seizure control in children with Dravet syndrome. We look forward to presenting further data in future publications and at medical conferences,” said Stephen J. Farr, Ph.D., President and CEO of Zogenix. “We expect top-line results from our second pivotal Phase 3 trial, Study 1504, which is nearing full enrollment, in the first half of 2018. We remain on track to submit applications for regulatory approvals in the U.S. and Europe in the second half of 2018.”
ZX008 is designated as an orphan drug in both the U.S. and Europe, and has received Fast Track designation in the U.S. for the treatment of Dravet syndrome.
About the ZX008 Dravet Syndrome Global Development Program
Study 1 is a prospective merged analysis of two identical double-blind, placebo-controlled studies, ZX008-1501 (US/Canada) and ZX008-1502 (Europe/Australia), designed to enroll approximately 40 patients per treatment group and includes patients from sites in the United States, Canada, Europe, and Australia. A total of 119 patients were randomized into one of two dose groups of ZX008, 0.2 and 0.8 milligrams per kilogram per day, or placebo. After a six-week baseline period, randomized subjects were titrated to their target dose over two weeks, and then held to that fixed dose for 12 weeks of maintenance treatment. The primary objective of the study was to demonstrate that ZX008 at the high dose is superior to placebo in controlling seizures based on the change in the frequency of convulsive seizures between baseline and the combined titration and maintenance periods. The percent of patients who achieve equal or greater than a 50% reduction in convulsive seizures, and measurement of the longest seizure-free interval, were key secondary endpoints. Patients who complete Study 1 are eligible to enter a long-term, open-label extension study.
Zogenix is conducting a second double-blind, randomized, two-arm pivotal Phase 3 trial, Study 1504, in which all patients will be taking stiripentol, valproate and clobazam as part of their baseline standard care. In February 2017, the Company announced the initiation of the safety and efficacy portion of Study 1504, which compares a single dose of ZX008 versus placebo across the titration and 12-week maintenance periods. Study 1504 will enroll 40 patients per treatment group.