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The new PDUFA action date has been set as June 25, 2020, a 3-month extension. The FDA informed Zogenix that additional data submission has constituted a major amendment to the NDA.
Stephen J. Farr, PhD
The FDA has extended the review period for Zogenix’s investigational Dravet syndrome treatment, fenfluramine (Fintepla), with the agency citing the need for additional time to assess additional data it requested from Zogenix, according to a recent announcement from the company.1
Its Prescription Drug User Fee Act (PDUFA) action date has been moved to June 25, 2020, a 3-month extension from its original date of March 25. The FDA informed Zogenix that additional data submission has constituted a major amendment to the NDA.
“We remain very confident in the data supporting our NDA submission, and look forward to continuing discussions with the FDA during the review process,” said Stephen J. Farr, PhD, president and CEO, Zogenix, in a statement. “We are committed to bringing this investigational therapy forward to help meet the needs of patients and families with Dravet syndrome.”
Notably, fenfluramine has had an eventful ride on its track to FDA review. Zogenix originally filed its NDA in April 2019, only to receive a refusal to file letter from the agency due to some missing and incorrect datasets. It was resubmitted in September 2019 after the company worked with the agency to clarify the issues identified.
The initial NDA submission was supported by results from 2 positive phase 3 trials, as well as an interim analysis from an ongoing open-label extension study, showing that fenfluramine was effective, meeting all primary and secondary endpoints. The study included 232 patients across a 24-month treatment period and showed that treatment with fenfluramine reduced seizures by 63.9% compared with placebo.2
At the 2019 American Epilepsy Society Annual Meeting, December 6-10, 2019 in Baltimore, Maryland, data from an additional open-label, phase 3 clinical study of adjunctive fenfluramine, which demonstrated an association between a significant reduction in convulsive seizure frequency and improvement in everyday executive function in patients with Dravet syndrome.
Executive function was evaluated based on score on the Behavior Rating Inventory of Executive Function (BRIEF), which was taken at baseline, and later updated to BRIEF2, including the Behavior Regulation Index (BRI), Emotion Regulation Index (ERI), Cognitive Regulation Index (CRI), Global Executive Composite, and Global Executive Composite (GEC) scores.
From baseline, patients who had year 1 BRIEF2 data and had 1 year of fenfluramine exposure (n=53) saw a -71.0% change in convulsive seizure frequency (range, -99.7%-55.0%). Among the participants, 24 (45%) achieved a ³75% reduction in convulsive seizure frequency compared to 11 patients who had <25% reduction in convulsive seizure frequency. The investigators observed a correlation between ERI (P = .032), GEC (P = .034) and CRI (P = .066) with change in convulsive seizure frequency. Meaningful improvements on ERI and GEC (P < .05) are parallel with the higher percentage of patients who experienced profound changes in convulsive seizure frequency.3
Zogenix also recently released the positive top-line results of its phase 3 Study 1601 of fenfluramine. The trial met its primary end point in the treatment of patients with Lennox-Gastaut syndrome (LGS), with the 0.7 mg/kg per day dose observed to be superior to placebo in reducing the frequency of drop seizures, based on the change between baseline and the titration and maintenance treatment period (P = .0012), in a cohort of 263 patients with uncontrolled seizures.4
Additionally, the lower dose of fenfluramine—0.2 mg/kg per day—was also linked to a reduction, though nonsignificant, in the frequency of drop seizures between the baseline and treatment periods (P = .0915).
1. Zogenix Announces FDA Extension of Review Period for FINTEPLA® in Dravet Syndrome [press release]. Emeryville, CA: Zogenix; Published February 27, 2020. Accessed February 27, 2020. globenewswire.com/news-release/2020/02/27/1991846/0/en/Zogenix-Announces-FDA-Extension-of-Review-Period-for-FINTEPLA-in-Dravet-Syndrome.html.
2. Zogenix announces FDA acceptance for filing of new drug application and priority review for fintepla for the treatment of dravet syndrome [news release]. Emeryville, CA: Zogenix. November 25, 2019. Accessed February 27, 2020. globenewswire.com/news-release/2019/11/25/1951951/0/en/Zogenix-Announces-FDA-Acceptance-for-Filing-of-New-Drug-Application-and-Priority-Review-for-FINTEPLA-for-the-Treatment-of-Dravet-Syndrome.html.
3. Bishop KI, Isquith PK, Gioia G, et al. Profound reduction in seizure frequency (>75%) leads to improved everyday executive function: analysis from a phase 3 study of ZX008 (fenfluramine HCL) in children/ young adults with Dravet syndrome. Presented at: American Epilepsy Society 2019 Meeting. December 6-10, 2019; Baltimore, Maryland. Abstract 2.438.
4. Zogenix Announces Positive Top-line Results from Global Pivotal Phase 3 Trial of FINTEPLA® for the Treatment of Lennox-Gastaut Syndrome [press release]. Emeryville, CA: Zogenix; Published February 6, 2020. Accessed February 27, 2020. zogenixinc.gcs-web.com/news-releases/news-release-details/zogenix-announces-positive-top-line-results-global-pivotal-phase.