Post hoc analysis of pooled and still blinded data from clinical trials (NCT02826863, NCT02682927, NCT02926898) shows that adjunctive treatment with fenfluramine (FFA) (ZX008; Zogenix, Emeryville, CA) for Dravet’s syndrome (DS) in children, age 2 to 18 years reduced generalized tonic-clonic seizure frequency by as much as 80%.
Children with DS typically have a high frequency of seizures, often experience cognitive decline, and have a higher frequency of sudden unexplained death in epilepsy (SUDEP), which is thought to be driven by the higher seizure frequency. Current treatments include stiripentol, clobazam, and valproate. However, fewer than 25% of patients achieve seizure control with these treatments, and over half continue to have 4 or more generalized tonic-clonic seizures per month.
Of note, no serious adverse events have been seen in these trials of FFA, including children treated for as long as 18 months, including no cardiac valvular disease or pulmonary arterial hypertension. Adverse events have been generally mild and included decreased appetite, lethargy, fatigue, somnolence, and diarrhea.
Seizure reduction has remained at similar rates in an open-label extension study (NCT02823145). Adjunctive treatment with FFA resulted in sustained, clinically meaningful mean reduction in convulsive seizure frequency of 63.6% (n = 158; P < .001) compared with baseline. The median reduction was higher for children under age 6 (75.5%; n = 42; P < .001) and slightly lower for children 6 years or more (60.1%; n = 116; P < .001).
The results described are further validated through use of Clinical Global Impression of Change-Caregiver and -Investigator (CGI-C; CGI-I) rating scales. Furthermore, a correlation between monthly convulsive seizure frequency (MCSF) reductions and CGI scores. This analysis showed that a 37.5% reduction in MCSF was associated with caregivers and investigators rating patients as much improved or very much improved.
Joseph Sullivan, MD, Department of Neurology, University of California San Francisco and investigator in some of the trials said, “This is a very effective and safe drug for a population with a highly drug-resistant form of epilepsy. Cardiac monitoring has been done every 3 months and no valvulopathies or pulmonary arterial hypertension were seen over up to 4 years of treatment. Loss of appetite has occurred at a higher frequency with FFA vs placebo, so it will be important to work with nutritionists and dietitians to ensure proper caloric intake if this occurs.”
A pharmacokinetic study of coadministration of FFA and cannabidiol (administered with food as CanniMed Oil 20:1 [20 mg/mL CBD + 1 mg/mL THC]; Aurora; Saskatoon, SK, Canada) suggested that dose adjustments would not be required for cotreatment with these 2 drugs. Coadminstration increased FFA Cmax by 10%; FFA had no significant effect on pharmacokinetics of cannabidiol. The same liver enzymes metabolize both FFA and cannabidiol. A specific formulation of cannabidiol (Epidiolex; GW Pharma, Carlsbad, CA) is already approved by the Food and Drug Administration (FDA) for treatment of Dravet syndrome in children, creating the potential for coadministration with FFA, if the latter is approved.
Improvements in everyday executive functions (ie, behavioral and emotional regulation) seen with FFA adjunctive treatment of children and young adults with DS were associated with improvements in quality of life.
These data were presented at the 48th Annual Meeting of the Child Neurology Society in Charlotte, NC October 23-26, 2019.
Ilana E. Green; Andrew M. Southerland, MD, MSc; and Bradford B. Worrall, MD, MSc
Ilka Kleffner, MD; Catharina C. Gross, PhD; Marius Ringelstein, MD; Jörg Rehrmann, MD; Markus Kraemer, MD; and Jan Dörr, MD
Kelly G. Gwathmey, MD