JAMA Neurology has published the results of study 1504 phase 3 study (NCT02926898) of the investigational drug, fenfluramine (ZX008, Fintepla), in participants with Dravet syndrome whose antiepileptic drug treatment regimens included stiripentol but who were still experiencing a high number of convulsive seizures. The study demonstrated that adding fenfluramine to these participant’s treatment regimens led to a significant and clinically meaningful (> 50%) reduction in monthly convulsive seizure frequency (MCSF).
Participants treated with fenfluramine achieved a 54% greater reduction in mean MCSF than those receiving the placebo (95% CI, 35.6%-67.2%; P<.001). Additionally, 54% of participants treated with FINTEPLA experienced a clinically meaningful (>50%) reduction in MCSF versus 5% with placebo (P<.001). Profound seizure reduction (>75% reduction in MCSF) was experienced by 35% of participants treated with fenfluramine compared to 2% with placebo (P=.003). The median longest seizure-free interval was 22 days (3.0-105.0) with fenfluramine and 13 days (1.0-40.0) with placebo (P=.004).
Fenfluramine was well-tolerated and demonstrated a safety profile consistent with the findings of a previous phase 3 study and findings of an ongoing open-label extension study. The most common adverse events in study 1504 were decreased appetite (19 participants taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Across all 3 studies, no participants exhibited clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension.
“Because it is common for physicians to use stiripentol for (people with Dravet syndrome), it was important to evaluate the benefit and tolerability of adding Fintepla to a stiripentol-inclusive treatment regimen in those patients who were still experiencing frequent convulsive seizures,” said study author, professor Rima Nabbout, MD, PhD, Department of Pediatric Neurology, Reference Center for Rare Epilepsies, Necker Enfants Malades Hospital, Paris, France, and Principal Investigator of Study 1504. “We found that adding Fintepla to a regimen containing stiripentol resulted in a significant and clinically meaningful reduction in monthly convulsive seizure frequency early and for the duration of the study period. Participants in the Fintepla arm also experienced longer seizure-free intervals, which is important as many were previously experiencing multiple seizures per week.”
Study 1504 was an international double-blind placebo-controlled phase 3 study of 87 people with Dravet syndrome, age 2 to19 years who were taking background antiepileptic drugs including stiripentol. Participants were randomly assigned to receive placebo (n=44) or fenfluramine 0.4 mg/kg/day (n=43). Eligible participants in the trial were experiencing seizures that were poorly controlled with their current antiseizure medications consisting of stiripentol plus clobazam and/or valproic acid. After a 6-week period to establish baseline seizure frequency, participants were randomized to receive fenfluramine starting at a dose of 0.2 mg/kg/day, twice daily with gradual blinded titration over a 3 week period to 0.4 mg/kg/d, maximum of 17 mg per day, over 3 weeks. Participants maintained their regimen for an additional 12 weeks at a stable dose, then either continued treatment in an open-label extension study or discontinued treatment.