In a global phase 3 clinical trial, fenfluramine (ZX008, Fintepla, Zogenix, Emeryville, CA) (Study 1601) reduced seizures in individuals with Lennox-Gastaut syndrome (LGS). A decrease in the frequency of drop seizures from baseline was observed for a lower dose of fenfluramine (0.2 mg/kg/day) compared with placebo, but this change did not reach statistical significance (P=.0915). Fenfluramine was generally well-tolerated, with the adverse events consistent with those observed in the 2 prior phase 3 studies in Dravet syndrome (DS).
The study showed a statistically significant reduction in the median percent change in monthly drop seizure frequency from baseline with fenfluramine compared with placebo. Participants taking fenfluramine 0.7 mg/kg/day achieved a median reduction of 26.5% compared with a median reduction of 7.8% in participants taking placebo (P=.0012). Using a parametric analysis, participants taking fenfluramine 0.7 mg/kg/day demonstrated a 26.5% greater reduction in mean monthly drop seizure frequency compared with placebo (P=.0034). The median percent reduction in monthly drop seizures between baseline and the treatment period for the lower study dose of fenfluramine (0.2 mg/kg/day), a secondary endpoint, was 13.2% and did not reach statistical significance compared with placebo (P=.0915).
“The results observed in this placebo-controlled study are indicative of the potential of fenfluramine to treat patients with refractory LGS. If approved, fenfluramine could represent an important new treatment option for these patients and their families in need.” said associate professor Kelly Knupp, MD, MSCS, FAES of Children’s Hospital Colorado, principal investigator for Study 1601.
Fenfluramine was generally well-tolerated in this study, with the adverse events consistent with those observed in the 2 prior phase 3 studies in DS. The incidence of participants who experienced at least one adverse event was 89.7% of participants in the fenfluramine 0.7 mg/kg/day group, 76.4% in the fenfluramine 0.2 mg/kg/day group and 79.3% in the placebo group. The most common adverse events (≥10%) in the fenfluramine treated groups were decreased appetite, somnolence, fatigue, vomiting, diarrhea, and pyrexia. The incidence of serious adverse events was 11.5% (n=10) in the 0.7 mg/kg/day group, 4.5% (n=4) in the 0.2 mg/kg/day group, and 4.6% (n=4) in the placebo group. Six participants in the 0.7 mg/kg/day group had an adverse event leading to study discontinuation compared with 4 participants in the 0.2 mg/kg/day group and 1 participant in the placebo group; the majority of these were considered treatment related. There was 1 death during the trial (0.7 mg/kg/day group) caused by SUDEP (sudden unexpected death in epilepsy), which was assessed by the investigator to be unrelated to the study drug.
No cases of valvular heart disease or pulmonary hypertension have been observed in Study 1601. A total of 247 (93.9%) participants entered the open-label extension phase.
Shailee S. Shah, MD, and Andrew McKeon, MD
Danielle S. Shpiner, MD; Crystal Dixon, MD; Melissa R. Ortega, MD; and Henry Moore, MD
Jason A. Ellis, MD; Benjamin W. Y. Lo, MD; Chirag G. Bhatia, BS; Yona Feit; Steven Mandel, MD; and Dana Shani, MD