A pooled analysis of 2 phase 3 trials of fenfluramine demonstrate the clinical potential of the drug for patients with Dravet syndrome.
Stephen Farr, PhD
Data from a pooled analysis of 2 phase 3 trials of fenfluramine (Fintepla: Zogenix) show a substantial reduction in the frequency of tonic-clonic (TC) seizures in patients with Dravet syndrome (DS). The results were presented at the 2019 Child Neurology Society Annual Meeting, October 23-26, 2019 in Charlotte, North Carolina.
The randomized, placebo-controlled studies included 206 patients (55% male; mean age, 9) and evaluated 3 different doses, a low dose of 0.2 mg/kg/day (n=39), a medium of 0.5 mg/kg/day (n=43), and a high dose of 0.8 mg/kg/day (n=40), compared with placebo (n=84). Fenfluramine was administered as adjunctive treatment to current antiepileptic drug regimens.
The median baseline monthly frequency of generalized TC seizures ranged from 8.0 to 12.3/month in the 4 dose groups. Each decreased by 80%, 64%, and 48% in the fenfluramine 0.8, 0.5, 0.2 mg/kg/day groups, respectively, compared with 10% in the placebo group.
Focal-to-bilateral TC seizures were experienced by fewer patients, with a median baseline frequency of 2.0 to 4.7/month. During treatment, median percent reductions in focal-to-bilateral TC seizure frequency were 97%, 33%, and 69% in the fenfluramine 0.8, 0.5, 0.2 mg/kg/day groups, respectively, compared with a 39% reduction in the placebo group.
In September, Zogenix resubmitted its new drug application (NDA) for fenfluramine following a refusal to file letter from the FDA back in April. At the time, the drug was deemed insufficient to permit a substantive review, with the FDA citing 2 reasons: Zogenix had failed to submit certain nonclinical studies needed to complete a full assessment of the chronic administration of fenfluramine, as well as an application that contained an incorrect version of a clinical dataset that prevented the completion of the review process.2
The NDA submission was backed by data from 2 phase 3 trials of 87 participants who were randomly assigned to receive 0.5 mg/kg/day of adjunctive fenfluramine, with a maximum dose of 20 mg titrated for 3 weeks, or placebo. In both studies, patients experienced improvements in the frequency of monthly convulsive seizures with little to no adverse effects. In the pooled analysis, the most common adverse events included decreased appetite, diarrhea, and fatigue. Notably, patients did not experience any valvular heart disease or pulmonary arterial hypertension.
“We believe that Fintepla, if approved, could become an important new treatment option for patients and families living with Dravet syndrome,” said Stephen J. Farr, PhD, president and chief executive officer of Zogenix, in a previous statement.
1. Devinsky O, Cross JH, Gil-Nagel A. ZX008 (Fenfluramine HCl Oral Solution) Significantly Reduces Frequency of Generalized TonicClonic Seizures in Dravet Syndrome: Pooled Analysis from Two Phase 3 Clinical Trials. Presented at: Child Neurology Society 2019 Annual Meeting. October 23-26, 2019: Charlotte, NC. Abstract #41.
2. Zogenix Receives Refusal to File Letter from U.S. Food and Drug Administration for FINTEPLA® New Drug Application [news release]. Emeryville, California: Zogenix; April 8, 2019. globenewswire.com/news-release/2019/04/08/1799322/0/en/Zogenix-Receives-Refusal-to-File-Letter-from-U-S-Food-and-Drug-Administration-for-FINTEPLA-New-Drug-Application.html. Accessed October 22, 2019.