Fenfluramine-Reduced Seizure Frequency in Dravet Improves Executive Function


Treatment with fenfluramine was associated with greater seizure reduction, which in turn improved executive function over time in patients with Dravet syndrome.

Peter Isquith, PhD

Peter Isquith, PhD

Results from an open-label extension study (NCT02823145) of fenfluramine (Fintepla; Zogenix) demonstrate a significant association between monthly convulsive seizure frequency (MCSF) reduction and improved executive function across a yearlong period in patients with Dravet syndrome (DS).1

This dataset included 72 of the 206 randomized patients. From pretreatment at baseline to Year 1, the median change in MCSF was 64.0% (range, —99.7 to 55.0). Additionally, change in MCSF correlated significantly with global executive composite (GEC; r = 0.23; P = .05), and showed correlation with behavior and emotion regulation indexes (BRI: r = 0.23, P = .06; ERI: r = 0.22, P = .07) but not cognitive regulation index (CRI; r = 0.18, P = .14).

The data that were accepted for presentation at the American Academy of Neurology (AAN) 2020 Annual Meeting showed that improvements in BRI, ERI, and GEC scores occurred more frequently in patients who achieved >75% MCSF reduction, compared to those in the <25% group (P <.05). The multicenter, long-term, open-label extension study aimed to evaluate the relationship between changes in MCSF and executive function in patients with DS, ages 5—18 years, after 1 year of add-on fenfluramine.

Patients included in the study were randomized to a fitted range between 0.2—0.7 mg/kg per day of fenfluramine or placebo for 14–15 weeks in 1 of 2 phase 3 clinical studies. Once patients entered the open-label extension, they received 0.2 mg/kg per day of fenfluramine, then were titrated to effect.

Study author Peter Isquith, PhD, developmental neuropsychologist, department of otolaryngology and communication enhancement, Boston Children’s Hospital, and colleagues, used Behavior Rating Inventory for Executive Function (BRIEF2) caregiver ratings as a way to evaluate executive function. Using Spearman’s Rho correlation coefficients, researchers compared change in BRIEF2 component scores from double-blind baseline to year 1 with MCSF reduction. The Wilcoxon-Mann-Whitney test was used to assess the BRIEF2 changes in patients achieving <25% vs >75% MCSF reduction.

READ MORE: Epidiolex Has Safe, Consistent Profile Over Long-Term in Tuberous Sclerosis Complex

Fenfluramine also had additional real-world data that were accepted for presentation at AAN 2020 which demonstrated that those with DS who are treated with fenfluramine had clinically meaningful responses to the therapy similar to what was observed in clinical development. Those data suggest that of the 23 patients included in the data, 15 (65%) reported meaningful global clinical improvement, defined as a rating of “very much improved” or “much improved.” Similar improvements were reported in cognition, behavior, and motor abilities by 56% (n = 13), 43% (n = 10), and 48% (n = 11) of the cohort, respectively.2

Previously, another analysis of this dataset with 53 patients treated with fenfluramine was presented at the 2019 American Epilepsy Society (AES) Annual Meeting.3

Just the month prior, the FDA had accepted the new drug application (NDA) for the oral solution of fenfluramine for the treatment of seizures associated with DS. In February of this year, the FDA extended the review period for fenfluramine, with the agency citing the need for additional time to assess additional data it requested from Zogenix. Originally, the Prescription Drug User Fee Act (PDUFA) action date was set for March 25, but it was pushed back to June 25, 2020.


1. Bishop K, Isquith P, Gioia G, Morrison G, Haney D, Gammaitoni A. Profound reduction in seizure frequency (>75%) leads to improved everyday executive function in patients with dravet syndrome at 1 year post-treatment with ZX008 (fenfluramine HCI oral solution): Analysis of data from the phase 3 clinical development program. Neurology. 2020;94(15 Suppl): 4257.

2. Perry MS, Wirrell E, Burkholder D, Galer BS, Gammaitoni A. Real-world Experience with ZX008 (Fenfluramine HCl) for the Treatment of Seizures in Dravet Syndrome: Initial Report from United States Expanded Access Program. Neurology. 2020;94(15 Suppl): 1985.

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.

Related Videos
Anton P. Porsteinsson, MD
Lidia Maria Veras Rocha Moura, MD, PhD, MPH, FAAN
Tarun Singhal, MD, MBBS
Jessica Ailani, MD
Jaime Imitol, MD
© 2024 MJH Life Sciences

All rights reserved.