Zogenix reported positive top-line results from a second confirmatory Phase 3 study investigating the use of ZX008 (low-dose fenfluramine hydrochloride) in treating children and young adults with Dravet syndrome, and said that it plans to request regulatory approval.
The Phase 3 trial (NCT02926898) — also known as study 1504 — enrolled 87 children (median age, 9) across the United States, Canada, and Europe. Patients were randomized to receive either ZX008 (43 patients) or placebo (44 patients) as a liquid solution added to a standard regimen of stiripentol (an anticonvulsant drug) plus other antiepileptic drugs.
ZX008 is a low-dose formulation of fenfluramine, a compound that can stimulate the release and activity of several neuroactive signaling molecules, including serotonin, which is known to have an antiepileptic effect.
Consistent with results reported in Zogenix’s two parallel Phase 3 studies (NCT02682927 and NCT02826863), ZX008 met the primary endpoint — a statistically significant reduction in mean convulsive seizure frequency — and key secondary endpoints.
Specifically, treatment with ZX008 resulted in a 54.7% greater reduction in mean monthly convulsive seizures compared to placebo. In fact, the median reduction in monthly convulsive seizure frequency was 62.7% in ZX008-treated patients and 1.2% in the placebo group.
These results led researchers to conclude that a daily regimen of 0.5 mg/kg of ZX008 — given twice daily in equally divided doses with food up to a maximum of 20 mg daily — plus stiripentol was beneficial in this patient population.
Among secondary study goals, ZX008 treatment achieved a clinically meaningful reduction in seizure frequency (defined as a reduction greater than 50% in convulsive seizures from study’s start). A statistically significant difference in seizure-free intervals was also seen between the two groups — the median longest seizure-free interval was 22 days in ZX008 patients, compared to 13 days in placebo patients.
“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,” Rima Nabbout, MD, the trial’s principal investigator with Necker Enfants Malades Hospital, France, said in a press release.
ZX008 was generally found to be well-tolerated, with similar adverse events as those observed in other Phase 3 studies.
There were no cases of cardiac valvulopathy (which can occur from exposure to fenfluramine, a component of ZX008) or pulmonary hypertension (increased blood pressure within the arteries of the lungs) during the study. The most common side effects in the ZX008 group included reduced appetite, diarrhea, fever, fatigue, and nasopharyngitis (swelling of the nasal passages and the back of the throat).
The rate of serious adverse events also was similar across treatment and placebo groups, with 14% of ZX008-treated group experiencing at least one such event compared to 15.9% of patients in the placebo group. Two patients in the treatment arm and one placebo patient left the study due to adverse events.
“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 U.S. and Europe in the fourth quarter of 2018. We are excited about ZX008’s potential to have a major impact in the treatment of patients with Dravet syndrome and their families,” said Stephen J. Farr, president and CEO of Zogenix.
ZX008 has been designated an orphan drug in the U.S. and Europe, as well as given a breakthrough therapy designation in the U.S. as a potential Dravet treatment.