Sunday, December 3, 2017

ZX008 in Dravet syndrome

Zogenix, Inc. (NASDAQ:ZGNX), 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.

1 comment:

  1. Le Bonheur Children's neurologists recently began enrolling patients in a new clinical trial of fenfluramine, which aims to help minimize the frequency of seizures for children with Dravet Syndrome.

    The trial is in its second phase, and Le Bonheur is one of only four children's hospitals in the region to offer the fenfluramine drug trial.

    Early results have found that patients who use fenfluramine have had fewer seizures, says Tracee Ridley-Pryor, MSN, RN, CCRC, the Neuroscience Institute's lead clinical research coordinator. Patients on the medication also have shown attention, behavior, learning comprehension and language development improvements.

    "The efficacy of fenfluramine has been demonstrated in the number of seizure-free days our patients have experienced while on the investigational medication, up to 29 and 31 seizure-free days, respectively," Ridley-Pryor said."For these families, this has been the greatest period of time their child has gone without a seizure since receiving a diagnosis of epilepsy."

    Kevin and Katie Peters-Larson's 3-year-old daughter, Maelee, is one of the children enrolled in the fenfluramine drug trial.

    Maelee had her first seizure at 4 months old, and her seizures increased in frequency as she aged. At her worst period, Peters-Larson said her daughter would suffer from hundreds of seizures a day, including tonic-clonic, myoclonic and grand mal seizures. Anti-seizure medications failed to slow her seizure activity and changing her diet didn't help either, said Peters-Larson. In 2016, neurologists near their Tulsa, Okla., home implanted a vagus nerve stimulator (UNS) but the device did little to reduce the amount of seizures.

    After running out of treatment options in Oklahoma, the Peters-Larson family then turned Le Bonheur for help. When Neurologist Stephen Fulton, MD, suggested that Maelee enroll in the hospital's new fenfluramine drug trial, Peters-Larson signed up.

    "We were excited about enrolling because nothing else was helping;' Peters-Larson said. "We needed to try something else."

    After adjusting the dosage of her new medication, Maelee was seizure free for 31 days — her longest stretch ever. Maelee's cognitive abilities also have improved.

    "Before she started taking (fenfluramine), she never had a day without a seizure," Peters-Larson said. "Without that constant electrical storm in her brain, she can now learn and retain information."

    In addition to taking fenfluramine, patients enrolled in the trial must also continue to take their anti-seizure medications and are required to return to Le Bonheur for monthly study visits.

    Fenfluramine trial at a glance:
    Phase two trial
    Treatment for seizures associated with Dravet Syndrome
    Early results show fewer seizures Shown to improve attention, behavior, learning comprehension and language development

    Le Bonheur Children’s Hospital Brain Waves Winter 2017