Fenfluramine Proves Durable in Dravet Syndrome Open-Label Extension

Ingrid Scheffer, MBBS, PhD, FRS, FAA, FAHMS

New data from an open-label extension trial, known as Study 1503 (NCT02823145), of fenfluramine (Fintepla; Zogenix) suggest that the treatment continued to provide both durable and significant reductions in monthly convulsive seizure frequency for patients with Dravet syndrome who were treated for up to 3 years.¹

In total, 38.2% of the patients experienced a ≥75% reduction and 63.4% of patients reported a ≥50% reduction in monthly convulsive seizure frequency over the course of the entire analysis period. At least 1 dose of fenfluramine was administered to 330 patients who enrolled (mean age, 9.0 years [±4.6]), with a median treatment duration of 631 days (range, 7–1086). A total of 282 patients reported >12 months of exposure to fenfluramine and 128 patients reported >24 months in the OLE.

“Fenfluramine’s ability to provide this profound degree of sustained efficacy over long periods of time may also have important implications for longer-term neurodevelopmental outcomes,” the authors, including Ingrid Scheffer, MBBS, PhD, FRS, FAA, FAHMS, Laureate Professor, and chair, Pediatric Neurology Research, University of Melbourne, wrote. Scheffer and colleagues presented their data virtually at the 2020 American Epilepsy Society (AES) Annual Meeting, December 4–8, 2020.

This open-label extension included patients who completed phase 3 controlled studies of fenfluramine, all of whom began treatment at 0.2 mg/kg/day regardless of starting dose received in the core studies. After 4 weeks, doses were titrated to effect and tolerability, up to 0.7 mg/kg/day (maximum 26 mg/day), or 0.4 mg/kg/day (maximum 17 mg/day) for those who were also receiving stiripentol. Seizure frequency was measured via hand-held e-diary, while effectiveness and safety were assessed monthly for the first 3 months, then quarterly.

The most common concomitant antiepileptic drugs utilized were valproate (80.6%), clobazam (72.7%), stiripentol (29.4%), topiramate (25.5%), and levetiracetam (25.5%).

READ MORE: Fenfluramine Demonstrates Efficacy in Lennox-Gastaut Syndrome in Phase 3 Results

The median percent reduction in monthly convulsive seizure frequency from baseline in the core studies compared to most recent visit was –64.5% (P <.001). Over the full analysis timeframe, 63.4% of subjects experienced a clinically meaningful reduction in monthly convulsive seizure frequency—defined as ≥50% reduction—and 38.2% reported profound reductions (defined as 75%). In total, 3 patients reported seizure-freedom over their entire time in the extension trial.

The safety analysis showed that reasons for discontinuation consisted of lack of efficacy (14.5%) and adverse events (AEs; 3.3%). The most common AEs, occurring at a rate ≥15%, included pyrexia (28.2%), nasopharyngitis (27.3%), decreased appetite (23.0%), decreased blood glucose (19.4%), diarrhea (18.2%), seizure (16.7%), echocardiogram abnormal (19.4%; limited to nonpathological trace/physiologic regurgitation), and upper respiratory tract infection (15.5%).

Notably, there were no reported cases of valvular heart disease (VHD) nor pulmonary artery hypertension (PAH) observed over the course of the OLE treatment period.

In October 2020, an analysis was presented as a poster at the Child Neurology Society and International Child Neurology Congress (CNS/ICNA) 2020 meeting, including data phase 3 and long-term extension studies of fenfluramine in pediatric patients (NCT02682927/NCT02826863, NCT02926898, NCT02823145). All told, using Receiver operator characteristic (ROC) analysis per the investigator assessment of CGI-I, 25.6% and 52.5% of the low- (0.2 mg/kg/day) and high-dose (0.7 mg/kg/day) 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.²

Additionally, a month prior, in September 2020, Zogenix announced the top-line results of its third phase 3 study—aptly named Study 3—of fenfluramine in Dravet syndrome were positive, corroborating the findings of the 2 prior phase 3 trials. Ultimately, the international, randomized, double-blind trial included 143 children and young adults and revealed that those treated with 0.7 mg/kg per day fenfluramine experienced a 64.8% greater reduction in mean monthly convulsive seizures compared to the placebo group (P <.0001). The median reduction in the monthly frequency of convulsive seizures was 73.7% for the fenfluramine group. Comparatively, the placebo group experienced a 7.6% monthly reduction.³

That study also expanded the evaluation of fenfluramine to more locales, this time including patients from Japan, in line with the company’s plans to submit a new drug application (J-NDA) there for the oral agent in 2021. The agent was approved in the US for the treatment of Dravet syndrome in June 2020.

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REFERENCES
1. Scheffer I, Devinsky O, Perry S, et al. Efficacy and tolerability of adjunctive fintepla (Fenfluramine hydrochloride) In an open-label extension study of dravet syndrome patients treated for up to 3 years. Presented at AES 2020 Virtual Meeting; December 4–8, 2020. Abstract 978.
2. 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.
3. Zogenix Announces Positive Top-Line Results from its Third Pivotal Phase 3 Clinical Trial (Study 3) of FINTEPLA® in Dravet Syndrome. News release. Emeryville, CA. Zogenix. Published September 10, 2020. Accessed September 22, 2020. https://www.biospace.com/article/releases/zogenix-announces-positive-top-line-results-from-its-third-pivotal-phase-3-clinical-trial-study-3-of-fintepla-in-dravet-syndrome