Phase 3 Trial Evaluating ZX008 for Dravet Syndrome Meets Primary Endpoint

A severe form of epilepsy that often presents before age 1 through frequent and fever-related (febrile) seizures, Dravet syndrome, is a devastating neurological disease characterized by moderate to severe cognitive impairment and intractable epilepsy in adulthood. In 85% of its cases, the disease is due to a mutation in the SCN1A gene, which facilitates the proper function of brain cells, while about 10% of cases have unknown cause.

In all cases, reducing the frequency of seizures and preventing status epilepticus is the main goal of treatment. Now, in a second confirmatory, double-blind, placebo-controlled, phase 3 study, a low-dose fenfluramine liquid solution, Zogenix, Inc’s ZX008, has displayed favorable results in 87 patients between the ages of 2 and 19, meeting its primary endpoint of a change from baseline in frequency of convulsive seizures as well as all key secondary endpoints and safety measures.

For the trial, patients were assigned to be a part of 1 of 2 treatment groups, where ZX008 (43) or placebo (44) was added to their stable background regimen of stiripentol plus other antiepileptic drugs. The drug was given at a dose of 0.5 mg/kg/day (maximum 20 mg/day) to account for a drug-drug interaction between stiripentol and ZX008.

Compared with the placebo (p<0.001), patients experienced a 54.7% greater reduction in mean monthly convulsive seizures as well as a median reduction of 62.7% in monthly convulsive seizure frequency (compared with 1.2% in placebo patients).

Furthermore, ZX008 was found to demonstrate a statistically significant improvement compared with placebo in both secondary measures; 53.5% of ZX008-treated patients experienced a 50% or greater reduction in monthly convulsive seizures, while 32.6% of ZX008-treated patients experienced a 75% or greater reduction. There was also a marked improvement noted in longest seizure-free survival, with a median of 22 days.

“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,” said professor Rima Nabbout, MD, PhD, department of Pediatric Neurology, Reference Center for Rare Epilepsies, Necker Enfants Malades Hospital, and Principal Investigator of Study 1504, in a recent statement.

Overall, the safety profile of ZX008 was favorable, with the drug being generally well tolerated. Neither cardiac valvulopathy nor pulmonary hypertension were experienced by patients at any point in the study, and no safety signal of any cardiovascular abnormality has been identified to date.

More specifically, the incidence of treatment-emergent adverse events, which paralleled those observed in Study 1, reinforced the efficacy observed in the trial with only a 2.2% difference observed between the ZX008-treated group and the placebo group. Decreased appetite, diarrhea, pyrexia, fatigue, and nasopharyngitis were among the most common adverse events associated with ZX008.

The incidence of serious adverse events also mirrored the slight difference observed between the ZX008-treated group and the placebo group in the incidence of emergent adverse events, with only a 1.8% difference between the two groups. Only 2 patients discontinued the study due to serious adverse events.

“The new results from the 1504 study provide further evidence of the efficacy of ZX008 in the treatment of seizures in patients with Dravet syndrome," added Joseph Sullivan, MD, director of the Pediatric Epilepsy Center in UCSF Benioff Children’s Hospital San Francisco, eclusively to Rare Disease Report®. "The median seizure reduction of 54.7% compared to placebo is in itself impressive. Furthermore, 32.6% of patients receiving ZX008 having a ≥75% reduction is one of the most clinically significant improvements we have seen with any treatment for this highly refractory group of patients who are deeply impacted by the frequency and severity of seizures associated with Dravet syndrome.”

Previously, ZX008 was granted an orphan drug designation in the United States and Europe for the treatment of Dravet syndrome; the drug also received a breakthrough therapy designation in the United States. In a meeting with US Food and Drug Administration (FDA) earlier this year, Zogenix, Inc also reviewed the planned New Drug Application (NDA) submission in Dravet syndrome in which the FDA affirmed Study 1 and Study 1504 were suitable as the clinical basis for the NDA submission.

“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,” Dr Nabbout concluded.