Zogenix Submits NDA for ZX008 for Dravet Syndrome

Stephen J. Farr, PhD, the president and CEO of Zogenix

Stephen J. Farr, PhD

Zogenix has completed its rolling submission of its New Drug Application (NDA) for ZX008 (Fintepla), its low-dose fenfluramine agent, for the treatment of seizures associated with Dravet syndrome.¹

The NDA is supported by data from 2 phase 3 trials in Dravet syndrome, as well as an interim analysis from the company’s ongoing open-label extension study, which includes 232 patients treated for up to 21 months. The data is also part of Zogenix’s Marketing Authorization Application submission to the European Medicines Agency.

“Our concurrent submissions to the FDA and EMA are the culmination of four years’ effort for Zogenix, our investigators, and the families who participated in the ZX008 clinical trial program,” said Stephen J. Farr, PhD, the president and CEO of Zogenix, 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.”

In 1 of the phase 3 studies of the treatment, ZX008 showed a median reduction of 62.7% in monthly convulsive seizures compared with a 1.2% reduction with placebo, as well as a mean monthly reduction in compulsive seizures of 54.7% compared with placebo. The study randomized 87 patients (median age, 9 years) to receive ZX008 (n = 43) or placebo (n = 44) after 6 months of observation. All patients were receiving stable background treatment with stiripentol plus other antiepileptic drugs. The Zogenix product was given at 0.5 mg/kg per day with a maximum dose of 20 mg and was titrated for 3 weeks.²

There were marked improvements in secondary end points with ZX008, including reductions in convulsive seizures of ≥50% and ≥75%. In total, 53.5% of those treated with ZX008 had a reduction in monthly compulsive seizures of ≥50% while just 6.8% did so with placebo.

As well, a ≥75% reduction was experienced by 32.6% of patients with ZX008 compared with 2.3% with placebo. The longest seizure-free interval was 22 days with the study drug and 13 days for placebo.

In the trial, ZX008 was well tolerated, with no patients experiencing cardiac valvulopathy or pulmonary hypertension. The rate of serious adverse events (AEs) was similar in each arm—14% with ZX008 compared with 15.9% with placebo. Ultimately, 2 patients discontinued treatment due to AEs in the ZX008 arm.

Some of the data from these studies were presented at the American Epilepsy Society’s 2018 annual meeting in New Orleans, Louisiana, where NeurologyLive spoke with Joseph Sullivan, MD, the director of the Pediatric Epilepsy Center at UCSF’s Benioff Children’s Hospital and an investigator in ZX008’s clinical development program, about the therapy. He emphasized that while the seizure reduction numbers are positive, the focus for him has been on the positives in the secondary end points related to the non-seizure outcomes.

“In Study 1 we also looked at the brief which is a questionnaire that looks at the executive function in these children,” Sullivan said. “It was really included in the study to basically understand if there was no negative impact of [ZX008] on these measures of executive function, but when we actually looked at the data it was a pleasant surprise to us that we actually saw improvements in some measures of an executive function in those that received drug compared to placebo, where those that were on placebo actually had a slight worsening.”

Sullivan hinted that while those reductions could be attributable to the reduction in seizures, it may also be due to the therapy’s mechanism of action. The agent is a serotonergic agent, which makes it the only antiepileptic agent of its kind, currently.

“Further, there are some animal data that suggests that that fenfluramine may act at on the SIMA-1 receptor which is involved in neurotransmitter release. There's a lot more work being done there, but even if that doesn't end up being a major mechanism, the serotonergic activity is clearly different from any of the other drugs, so it really represents a potential new class

in antiepileptic drug therapies,” he added.

ZX008 is also being investigated in Lennox-Gastaut syndrome (LGS), for which a phase 3 trial is ongoing.

REFERENCES

1. Zogenix Submits New Drug Application to U.S. Food & Drug Administration and Marketing Authorization Application to European Medicines Agency for FINTEPLA® for the Treatment of Dravet Syndrome [press release]. Emeryville, CA: Zogenic, Inc; Published February 6, 2019. globenewswire.com/news-release/2019/02/06/1711347/0/en/Zogenix-Submits-New-Drug-Application-to-U-S-Food-Drug-Administration-and-Marketing-Authorization-Application-to-European-Medicines-Agency-for-FINTEPLA-for-the-Treatment-of-Dravet-S.html. Accessed February 6, 2019.

2. Zogenix Announces Positive Top-line Results from Second Pivotal Phase 3 Clinical Trial of ZX008 in Dravet Syndrome [press release]. Emeryville, CA: Zogenix, Inc; Published July 12, 2018. globenewswire.com/news-release/2018/07/12/1536420/0/en/Zogenix-Announces-Positive-Top-line-Results-from-Second-Pivotal-Phase-3-Clinical-Trial-of-ZX008-in-Dravet-Syndrome.html. Accessed February 6, 2019.