Today, Zogenix, Inc. announced positive top-line results from its Phase 3 clinical trial testing ZX008 (low-dose fenfluramine hydrochloride) to control seizure activity in patients with Dravet syndrome.
In the study, ZX008, at doses of 0.2 and 0.8 mg/kg/day, reduced the frequency of convulsive seizures in Dravet syndrome patients who averaged about 40 seizures per month before the study. The 0.8 mg/kg/day dose was especially effective, with that group having a 63.9% reduction in mean monthly convulsive seizures compared to placebo (P < .001).
Dravet syndrome is a rare pediatric epilepsy disorder and is often-associated with drug-resistant seizures and a high mortality rate. It almost always begins in the first year of life in an otherwise healthy infant. Patients with Dravet syndrome can present with a wide variety of seizure types in addition to suffering developmental delays; because of that, research is currently aimed at finding the best combination of medicines to treat and/or prevent seizures.
At present, there are no approved orphan drugs to treat this condition.
Fenfluramine is an indirect serotonin agonist and sigma-1 antagonist that was previously marketed as an anti-obesity drug until it was taken off the market in 1997 due to reports of valvular heart disease and pulmonary hypertension in women taking the medications at doses generally in the range of 60 – 120 mg per day.
ZX008 is being developed by Zogenix as a low dose version of flenfluramine and moving forward, it appears their 0.8 mg.kg/day will be the dose used based on the latest clinical trial results.
The completed study was a randomized, double blind, placebo-controlled, Phase 3 study in which 119 Dravet syndrome children (median age 8 years; range2 – 18 years) received 1 of 3 treatments: 1) ZX008 0.8 mg/kg/day (30 mg maximum daily dose; n=40); 2) ZX008 0.2 mg/kg/day (n=39); or 3) placebo (n=40).
The primary outcome measure was a 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 and the study showed that patients taking ZX008 0.8 mg/kg/day had a 63.9% reduction in mean monthly convulsive seizures compared to placebo (P
Patients taking ZX008 0.2 mg/kg/day also showed a reduction in mean monthly convulsive seizures of 33.7% compared to placebo (P
Details of the adverse events have not been provided by the company but they did note that the drug was generally well tolerated with the incidence of serious adverse events was similar in the 3 treatment groups [12.5% (n=5) in the 0.8 mg/kg/day group; 10.3% (n=4) in the 0.2 mg/kg/day group; and 10.0% (n=4) in the placebo group]. Five patients in the 0.8 mg/kg/day group had an adverse event leading to study discontinuation. Cardiac safety monitoring throughout the study showed no evidence of cardiac valvulopathy or pulmonary hypertension.
In a new release
, Joseph Sullivan M.D., director of the Pediatric Epilepsy Center in UCSF Benioff Children’s Hospital San Francisco, and Principal Investigator in the U.S. portion of the study said, “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.”
Moving forward, the company will continue with their second Phase 3 study involving the administration of ZX008 in Dravet patient who are also taking stiripentol, valproate and clobazam as part of their baseline standard care. Results from that trial are expected in 2018 and the company plans to submit applications for drug approval in the United States and Europe in the second half of 2018.
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