NDA Submitted to FDA for Low-dose Fenfluramine Therapy for Dravet Syndrome

Zogenix is seeking approval for its low-dose fenfluramine therapy, ZX008 (Fintepla), for the treatment of seizures associated with Dravet syndrome.

Zogenix has submitted a New Drug Application (NDA) to the FDA for its drug candidate ZX008 (Fintepla), low-dose fenfluramine, for the treatment of seizures associated with Dravet syndrome, according to a press release.

The company also submitted a Marketing Authorization Application to the European Medicines Agency (EMA).

Dravet syndrome is a difficult-to-treat form of epilepsy that often manifests in infancy. The disease is associated with frequent, severe, and potentially life-threatening seizures, developmental delay, and cognitive impairment.

Fenfluramine was previously sold as an appetite suppressant before it was withdrawn from the market in 1997 due to concerns about its potential link to heart valve problems. The applications are based on data from phase 3 clinical trials evaluating ZX008 in Dravet syndrome and an interim analysis from an ongoing open-label extension (OLE) study, which included 332 patients treated for up to 21 months.

Positive phase 3 results on the efficacy and safety of ZX008 were previously presented at the 72nd American Epilepsy Society Annual Meeting.

Study 1504, which evaluated the efficacy and safety of ZX008 in Dravet syndrome, included 87 patients who were taking a background anti-epileptic drug regimen that included stiripentol. Patients were either randomized to placebo or ZX008 0.5 mg/kg/day. After a 6-week baseline observation period, patients were titrated to their target dose over 3 weeks and remained at that fixed dose for 12 weeks.

According to the findings, ZX008 demonstrated significant efficacy when added to a stiripentol regimen in children and young adults with Dravet syndrome.

Results from Study 1503 showed durability of efficacy and no cardiac toxicity for ZX008 in Dravet syndrome. The study included 232 patients in the ongoing OLE trial. The median duration of treatment with ZX008 was 256 days and the range was 58 to 634 days.

Some of the key findings include:

  • In Study 1504, the odds of achieving a clinically meaningful or substantial reduction in convulsive seizure frequency were 26 and 24 times higher, respectively, among patients treated with ZX008 0.5 mg/kg/day than in patients treated with a placebo.
  • Data from Study 1504 showed a statistically significant difference in seizure-free intervals, with a median longest seizure-free interval of 22 days in patients treated with ZX008 0.5 mg/kg/day versus 13 days for patients in the placebo group.
  • In Study 1503, the median percent reduction in monthly convulsive seizure frequency over the OLE treatment period was 66.8% compared with baseline frequency. Over the same period, 64.4% of children and young adults demonstrated a >50% reduction in convulsive seizure frequency and 41.2% demonstrated a >75% reduction.

The safety profile for ZX008 was consistent across the clinical studies. No patient developed valvular heart disease or pulmonary arterial hypertension at any time after daily treatment with ZX008.

“Our concurrent submissions to the FDA and EMA are the culmination of 4 years’ effort for Zogenix, our investigators, and the families who participated in the ZX008 clinical trial program,” Stephen J. Farr, president and chief executive officer of Zogenix, said in a statement. “We are honored to have partnered with such dedicated people to develop a potential new treatment for this rare and often catastrophic disease and look forward to working closely with the FDA and EMA during the review process.”

A phase 3 trial is also ongoing to study ZX008 in Lennox-Gastaut syndrome, according to the press release.

References

Zogenix Submits New Drug Application to US Food & Drug Administration and Marketing Authorization Application to European Medicines Agency for Fintepla for the Treatment of Dravey Syndrome [news release]. Zogenix. https://zogenixinc.gcs-web.com/news-releases/news-release-details/zogenix-submits-new-drug-application-us-food-drug-administration. Accessed February 11, 2019.

Zogenix Announces Positive Phase 3 Trial Results on the Efficacy and Safety of Fintepla (ZX008) in Dravey Syndrome [news release]. Zogenix. https://zogenixinc.gcs-web.com/news-releases/news-release-details/zogenix-announces-positive-phase-3-trial-results-efficacy-and. Accessed February 11, 2019.