Fenfluramine reduced monthly convulsive seizure frequency by 54% compared with placebo in patients on medication regimens including stiripentol, with a significant proportion of those experiencing a meaningful or profound reduction.
Rima Nabbout, MD, PhD
New results of Study 1504 suggest that fenfluramine (Fintepla; Zogenix) could be a safe and effective new treatment option for patients with Dravet syndrome taking stiripentol who retain uncontrolled seizures.1
A dose of 0.4 mg/kg per day of oral fenfluramine reduced mean monthly convulsive seizure frequency by 54% compared with placebo in patients on medication regimens including stiripentol, and a significantly larger proportion of those taking fenfluramine experienced a meaningful or profound reduction.
“Fenfluramine may represent an important, effective new treatment option for patients with Dravet syndrome and seizures inadequately controlled on stiripentol-inclusive AED regimens,” wrote principal investigator Rima Nabbout, MD, PhD, Department of Pediatric Neurology, Reference Center for Rare Epilepsies, Necker Enfants Malades Hospital, and colleagues.
The investigators detailed that prior trials have suggested that stiripentol, while effective in reducing seizure frequency, fail to prevent seizures completely, even used in combination with clobazam and valproate. “In 1 study, despite treatment with stiripentol and 3 to 4 other AEDs, 79% of patients with Dravet syndrome continued to experience weekly or monthly seizures at follow-up a median of 8 years in length,” Nabbout and colleagues wrote.
In total, the double-blind, parallel-group, placebo-controlled, phase 3 randomized clinical study enrolled 87 patients with a mean age of 9.1 years and with a baseline frequency of at least 25 seizures per month and randomized them to either fenfluramine (n = 43) or placebo (n = 44).
After a 3-week titration period and 12 weeks of stable dosage, those treated with fenfluramine achieved the aforementioned 54% reduction (95% CI, 35.6—67.2; P <.001) compared to placebo. All told, 54% (n = 23) of those on fenfluramine achieved a ≥50% reduction in monthly convulsive seizures compared to 5% (n = 2) of those in the placebo group (P <.001), and 35% (n = 15) of the fenfluramine group achieved a ≥75% reduction compared to 2% (n = 1) of the placebo group (P = .003)
“The magnitude of treatment outcome is further highlighted by the fact that significantly more patients with added fenfluramine vs placebo experienced reductions in monthly convulsive seizure frequency that were clinically meaningful and profound, which are magnitudes of response not commonly seen in Dravet syndrome,” Nabbout and colleagues wrote.
The median longest seizure-free interval was 22 days (range, 3.0—105.0) with fenfluramine and 13 days (range, 1.0–40.0) with placebo (P = .004).
The median percentage reduction from baseline in monthly convulsive seizure frequency in the fenfluramine group was 63.1% (range, −100.0 to 115.0), compared with 1.1% (range, −82.8 to 435.1) in the placebo group during the combined treatment and maintenance periods (P <.001).
“Both caregivers and parents and investigators reported statistically significant differences between treatment groups in any improvement (i.e., those rated minimally improved or better),” the authors detailed.
The most common adverse events (AEs) were decreased appetite (fenfluramine: 44% [n = 19]; placebo: 11% [n = 5]), fatigue (fenfluramine: 26% [n = 11]; placebo: 5% [n = 1]), diarrhea (fenfluramine: 23% [n = 10]; placebo: 7% [n = 3]), and pyrexia (fenfluramine: 26% [n = 11]; placebo: 9% [n = 4]). “Importantly, no patient developed valvular heart disease or PAH, and all echocardiograms in all patients demonstrated normal valve function without observation of abnormal valve morphology,” investigators wrote.
Additionally, treatment-emergent AE-associated discontinuations occurred in 3 patients. Two patients (4.5%) receiving placebo and 9 patients (20.9%) receiving fenfluramine experienced weight decreases of ≥7% from baseline. Of those, 5 were also receiving topiramate.
In November, Zogenix’s new drug application (NDA) for the therapy was accepted by the FDA, with a Prescription Drug User Fee Act (PDUFA) target action date of March 25, 2020. The NDA was supported by results from 2 positive phase 3 trials showing that fenfluramine was effective, meeting all primary and secondary end points.2
“The FDA’s acceptance for the filing of the NDA under priority review for our investigational product, Fintepla, represents a significant milestone in its development,” said Stephen J. Farr, PhD, president and CEO of Zogenix, in a statement. “We are excited to continue working with the FDA with the goal of bringing Fintepla to Dravet syndrome patients and their families in need as quickly as possible.”
1. Naboout R, Mistry A, Zuberi S, et al. Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial. JAMA Neurol. Published online December 2, 2019. doi: 10.1001/jamaneurol.2019.4113.
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. 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. Accessed December 4, 2019.