In double-blind randomized placebo-controlled clinical trials, the investigational drug fenfluramine (Fintepla; Zogenix, Emeryville, CA) resulted in clinically meaningful (50% or more reduction) and profound (75% or more reduction) seizure reduction for people with Dravet syndrome. In Study 1 (NCT02682927, NCT02826863), profound seizure reduction was experienced by 50% of participants treated with fenfluramine compared with 3% of those treated with placebo (P=.003); 50% of those treated with fenfluramine experienced more than a 68% seizure reduction vs 13% of those treated with placebo (P<.001). Achieving 75% seizure reduction also correlated with changes in cognitive, emotional, and behavioral regulation as measured on BRIEF, whereas those who had 25% seizure reduction had improvements only in the behavioral regulation submeasure.
In addition to profound or clinically meaningful seizure reduction, participants treated with fenfluramine (.07 mg/kg/d) had 33 more days without seizures than those treated with placebo The median longest seizure-free interval for those treated with fenfluramine (.07 mg/kg/day) vs placebo was 25 vs 9.5 days (P=.001).
For those who enrolled in the open-label extension trial and had at least 1 year of treatment with fenfluramine (n = 53), seizure reduction correlated with a 10-point improvement in executive function, considered to be clinically meaningful. In contrast, those who had only a 25% seizure reduction did not have improved executive function.
In these trials, baseline seizure frequency was measured for all participants over a 6-week period before being they were randomly assigned to receive 1 of 2 different doses of fenfluramine or placebo for a 14-week period. Participants in the trials had the BRIEF test at baseline and at the end of the blinded period. For those who enrolled in the open-label extension trials, the BRIEF was also administered after 1 year of treatment.
Fenfluramine is a 5HT2A selective serotonin reuptake inhibitor that, if approved, will be the first serotonergic antiseizure medication (ASM). This novel mechanism of action for an ASM may explain the profound and clinically meaningful seizure reduction rate and increase in seizure free days and intervals.
Joseph Sullivan, MD Department of Neurology, University of California San Francisco and investigator in some of the trials, said “To achieve 75% reduction in seizure frequency suggest we can set the bar higher and strive for better seizure control for all people with Dravet syndrome. The mean age of participants in the study of executive function was 10 years and because we believe that the effect of seizures on cognition is cumulative, it is exciting to consider the impact that early treatment with fenfluramine may have not just on seizure reduction but also on neurodevelopment for people with Dravet syndrome over time.”
Olivia Reese; Rimas V. Lukas, MD; and Katherine S. Carroll, MD
Harold P. Adams Jr., MD
Ilka Kleffner, MD; Catharina C. Gross, PhD; Marius Ringelstein, MD; Jörg Rehrmann, MD; Markus Kraemer, MD; and Jan Dörr, MD