PHILADELPHIA — Cannabidiol (Epidiolex) as an add-on anticonvulsant treatment cut convulsive seizures nearly in half among children with Dravet syndrome, a dose-ranging phase III placebo-controlled study found.
After 14 weeks, two doses showed similar efficacy, according to Ian Miller, MD, of Nicklaus Children’s Hospital in Miami, and colleagues in an abstract that will be presented at the Emerging Sciences session of the American Academy of Neurology meeting next week.
Convulsive seizures decreased by 46% in children taking 20 mg/kg/day and 49% for children taking 10 mg/kg/day of cannabidiol, compared with 27% for placebo, they reported. Elevated transaminases and certain adverse events were higher in patients taking cannabidiol 20 mg/kg/day, and discontinuations due to adverse events occurred only in that group.
“Based on these results, dose increases above 10 mg/kg per day should be carefully considered based on the effectiveness and safety for each individual,” Miller said in a statement.
“The children in this study had already tried an average of four epilepsy drugs with no success and at the time were taking an average of three additional drugs, so to have this measure of success with cannabidiol is a major victory,” he added.
Dravet syndrome is an infantile-onset developmental and epileptic encephalopathy associated with drug-resistant seizures. Epidiolex is a pharmaceutical formulation of highly purified cannabidiol in an oral solution and was approved by the FDA last year to treat Dravet syndrome and Lennox-Gastaut Syndrome, another rare form of epilepsy.
Cannabidiol is a component of the Cannabis sativa plant that does not cause the intoxication that comes from tetrahydrocannabinol (THC). It is structurally unrelated to other anti-seizure medications and its anticonvulsant mechanism is unknown.
In this multi-center, randomized, double-blind trial (GWPCARE2), researchers studied 199 patients with Dravet syndrome: 67 received cannabidiol 20 mg/kg/day, 67 received cannabidiol 10 mg/kg/day, and 65 received placebo. The primary endpoint was the change in convulsive seizure frequency over a 14-week treatment period, compared with a 4-week baseline.
The mean age of patients was 9 years, and patients were taking a median of three antiepileptic drugs, after having discontinued a median of four drugs.
In both cannabidiol groups, the percentage reduction in convulsive seizures was higher compared with placebo (P=0.0299 for 20 mg/kg/day; P=0.0095 for 10 mg/kg/day). The reduction in total seizures also was higher.
The incidence of adverse events was similar across all groups (90% for the 20-mg dose, 88% for the 10-mg dose, and 89% for placebo) and most commonly included decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Serious adverse events were reported in 25% of the 20-mg group, 20% of the 10-mg group, and 15% of the placebo group. Only in the 20-mg group did patients discontinue because of serious adverse events (7%).
Elevated transaminases exceeding three times the upper limit of normal occurred in 19% of the 20-mg group and 5% of the 10-mg group, but none had elevations in bilirubin; all were taking concomitant valproate and all elevations resolved. There were no deaths, the researchers reported.
Miller will present detailed findings of this study at the Pennsylvania Convention Center Poster Hall, at 11:45 a.m. ET on Tuesday, May 7. The research adds to an expanding bank of literature about Dravet syndrome and cannabidiol; earlier this year, an open-label extension trial showed that long-term cannabidiol treatment over a median of 274 days had an acceptable safety profile and led to sustained reductions in seizure frequency.
The study was supported by GW Research, operating in the U.S. through its affiliate, Greenwich Biosciences.
Miller disclosed relevant relationships with Insys pharmaceuticals, GW Pharma, the TS Alliance, the DS Foundation, Visualase, NeuroBlate, Zogenix, and Ultragenyx. Co-authors disclosed multiple relevant relationships with industry including Greenwich Biosciences.