Fenfluramine Shows Durability in Monthly Convulsive Seizure Reduction

Bradley S. Galer, MD

New data published at the Child Neurology Society and International Child Neurology Congress (CNS/ICNA) 2020 meeting suggest that treatment with fenfluramine (Fintepla; Zogenix) represents an important new treatment option for patients with Dravet syndrome and offers a favorable percentage of patients an opportunity to reduce monthly convulsive seizure frequency.^1-3

The first poster presentation explored fenfluramine’s efficacy and durability in treating Dravet syndrome in an open-label extensions (OLE) study, the findings of which demonstrated a median reduction in monthly convulsive seizures of 63% (P <.001).² The second poster’s results suggest that for every 2–3 patients treated with fenfluramine, 1 achieved a reduction in monthly convulsive seizure frequency of ≥50% or ≥75% compared with placebo (Cohen’s d ≈ 0.8).³

“In addition to the significant convulsive seizure reductions seen in all three multi-national phase 3 studies of Fintepla in Dravet syndrome, we are proud to collaborate with expert clinician investigators to show the durability of the clinically meaningful seizure reduction that FINTEPLA provided for patients treated for up to 2 years,” said Bradley S. Galer, MD, executive vice president and chief medical officer, Zogenix, in a statement.¹ “Furthermore, new post-hoc data analysis from our studies demonstrated that for every 2 to 3 patients treated with Fintepla, 1 patient achieved ≥75% (profound) convulsive seizure reduction compared with placebo. We believe these new data analyses further showcase the clinical value that Fintepla provides for many Dravet syndrome patients and their families.”

The ongoing OLE assessment, known as Study 1503 (NCT02823145), included 330 patients with a mean age of 9 years (standard deviation [SD], 4.6) and a median treatment duration of 445 days. In total, 8% (n = 26) of patients received a mean daily dose of up to 0.2 mg/kg per day, while 27% (n = 90) received >0.2 mg/kg to <0.3 mg/kg, 37% (n = 123) received 0.3 mg/kg to 0.5 mg/kg, and 28% (n = 91) received >0.5 mg/kg to 0.7 mg/kg.²

In total, 61.7% (n = 204) and 37.1% (n = 123) of patients reported a ≥50% and a ≥75% reduction in monthly convulsive seizure frequency, respectively, during the entire 2-year OLE period. Additionally, 1.9% (n = 6) patients reported complete seizure freedom, with a mean duration of 285 days (median, 193 days).

Additionally, fenfluramine was deemed generally well-tolerated, with the most common treatment-emergent adverse events (AEs) being nasopharyngitis (23.3%; n = 77), pyrexia (23%; n = 76), decreased appetite (21.2%; n = 70), and diarrhea (15.2%; n = 50). In total, 93.3% (n = 308) of patients reported an AE. No cases of valvular heart disease or pulmonary arterial hypertension were reported.

WATCH NOW: Anticonvulsants to Treat Epilepsy and Alternatives

The second poster featured a post hoc analysis that took data from phase 3 and long-term extension studies of fenfluramine for the treatment of Dravet syndrome in pediatric patients (NCT02682927/NCT02826863, NCT02926898, NCT02823145). The patient population included 119 total patients from Study 1 with monthly convulsive seizure frequency data at Visit 12 (roughly Week 14), and the corresponding Clinical Global Impression of Improvement (CGI-I) data for 112 caregivers and 114 investigators. Additionally, there were 53 patients in the OLE who completed ≥1 year of treatment and had both pre-randomization baseline and Year 1 Behavior Rating Inventory of Executive Function (BRIEF 2) data available. Patients were treated with 0.2 mg/kg per day, 0.7 mg/kg per day, or placebo.³

All told, using Receiver operator characteristic (ROC) analysis per the investigator assessment of CGI-I, 25.6% and 52.5% of the low- and high-dose groups were deemed very much improved compared to 5% of the placebo group, with a reduction in monthly convulsive seizure frequency of 68%. This group was defined as deriving “profound” benefit. Likewise, the caregiver assessment of CGI-I, a “profound” benefit was achieved by 28.2% and 60% of the treatment groups, respectively, for a reduction of 60% in monthly convulsive seizures.

Patients who achieved what was defined as a “clinically meaningful” benefit were identical for both investigator and caregiver assessment of CGI-I. Those respective figures were 46.2% and 77.5% for the treatment groups and 12.5% for the placebo group, with a 44% reduction in monthly convulsive seizure frequency.

In a pooled analysis of active and placebo subjects at Year 1, more patients (24 of 53 patients; 45%) achieved profound (≥75%) compared to minimal (<25%) levels of monthly convulsive seizure frequency reduction (11 of 53 patients; 21%).

A profound reduction in monthly convulsive seizure frequency corresponded with the number-needed-to-treat of 2 to achieve these levels for patients receiving fenfluramine 0.7 mg/kg/day. In a second randomized controlled trial (Study 2), which assessed adjunctive fenfluramine in patients taking stiripentol), the number-needed-to-treat of 3 was observed at the ≥75% responder level.

REFERENCES
1. Zogenix Presents New Data for FINTEPLA® in Dravet Syndrome at CNS 2020. News release. Emeryville, CA. Zogenix. Published October 15, 2020. Accessed October 23, 2020. zogenixinc.gcs-web.com/news-releases/news-release-details/zogenix-presents-new-data-finteplar-dravet-syndrome-cns-2020
2. Sullivan J, Auvin S, Pringshelm M, et al. Long-Term (2-Year) Safety and Efficacy of Adjunctive ZX008 (Fenfluramine HCl) for Dravet Syndrome: Interim Results of an Ongoing Open-Label Extension Study. Presented at CNS 2020. PL30.
3. Sullivan J, Dlugos D, Nabbout R, et al. Number needed to treat (NNT) with fenfluramine to achieve a clinically meaningful reduction in convulsive seizure frequency in patients with Dravet syndrome. Presented at CNS 2020. PL31.