The FDA cited 2 deficiencies in the NDA: certain nonclinical studies were not included to allow for assessment of chronic administration of fenfluramine; and an incorrect version of the clinical data was submitted.
Stephen J. Farr, PhD
The FDA has issued Zogenix a refusal to file letter regarding its new drug application for ZX008 (fenfluramine hydrochloride, Fintepla) for treatment of seizures associated with Dravet syndrome.
While under preliminary review, the FDA determined that the new drug application was not sufficiently complete to permit a substantive review. The agency cited 2 reasons for the decision: the first, being that certain nonclinical studies were not submitted to allow assessment of the chronic administration of fenfluramine; second, the application contained an incorrect version of a clinical dataset that prevented the completion of the review process necessary to support the new drug application filing. The FDA did not request or recommend additional clinical efficacy or safety studies.
Zogenix plans to seek guidance from the FDA and schedule a Type A meeting in order to clarify and respond to the issues identified in the refusal to file letter.
“We remain highly confident in Fintepla’s clinical profile demonstrated in the phase 3 program in Dravet syndrome and are committed to advancing the product candidate as a potential new treatment option for this and other rare and often catastrophic epileptic encephalopathies,” Stephen J. Farr, PhD, president and chief executive officer, Zogenix, said in a statement.1 “We are fully committed to working with the FDA as quickly as possible to address the open issues and clarify the path to successfully re-filling our application.”
The new drug application, submitted February 5, 2019, was backed by data from 2 phase 3 trials in Dravet syndrome and an interim analysis from the ongoing open-label extension study that includes 232 patients treated for up to 21 months with ZX008. This data is also part of the company’s marketing authorization application submission to the European Medicines Agency (EMA), which was previously accepted for review. Zogenix anticipates a potential approval decision from the EMA in the first quarter of 2020.
In one of the phase 3 studies, 87 participants were randomly assigned to receive 0.5 mg/kg per day of ZX008 (n=43) with a maximum dose of 20 mg titrated for 3 weeks or placebo (n=44) after 6 months of observation. All participants were receiving a stable background treatment with stiripentol in addition to other antiepileptic drugs. Researchers reported that ZX008 demonstrated a median reduction of 62.7% in monthly convulsive seizures compared with a 1.2% reduction with placebo, in addition to a mean monthly reduction in convulsive seizures of 54.7% compared with placebo.2
There were improvements reported in secondary endpoints, including reductions in convulsive seizures of ≥50% and ≥75%. In all, 53.5% (P <.001) of participants treated with ZX008 reported a reduction in monthly convulsive seizures of ≥50%, while 6.8% reported the same finding with placebo. A ≥75% reduction was experienced by 32.6% (P = .004) of participants in the ZX008 arm compared with 2.3% in the placebo arm. Researchers reported that the longest seizure-free interval was 22 days (P <.005) with ZX008 and 13 days with placebo.
In this trial, ZX008 was well tolerated and no participants experienced cardiac valvopathy or pulmonary hypertension. The rate of serious adverse effects was similar in ZX008 and placebo (14% and 15.9%, respectively). It was reported that 2 participants discontinued treatment due to adverse effects in the ZX008 arm.
ZX008 is also being investigated in Lennox-Gastaut syndrome, for which a phase 3 trial is ongoing.
Receives Refusal to File Letter from
Food and Drug Administration for FINTEPLA® New Drug Application [news release]. Emeryville, Calif.: Zogenix; April 8, 2019. globenewswire.com/news-release/2019/04/08/1799322/0/en/Zogenix-Receives-Refusal-to-File-Letter-from-U-S-Food-and-Drug-Administration-for-FINTEPLA-New-Drug-Application.html. Accessed April 9, 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.