The therapy is a plant-derived cannabidiol being developed for patients with treatment-resistant forms of epilepsy including Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, and infantile spasms.
Data on the Phase 2 CARE1 trial (NCT02091206) were published in the journal Neurology. The study, “Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome,” showed Epidiolex was generally well-tolerated by patients.
The trial was divided into two parts: Part A primarily assessing Epidiolex’s safety and target dose, and Part B evaluating its anti-epileptic effectiveness at the chosen target dose.
This study reports on the safety results and preliminary pharmacokinetics of Part A, evaluated in a group of children with Dravet syndrome.
A total of 34 patients, between 4 and 10 years old recruited in the U.S. and U.K., were randomized to receive Epidolex, at 5, 10, or 20 mg/kg/day, or placebo twice daily for 21 days. The trial included a four-week initial observation period, three weeks of treatment, a 10-day tapering-off period, and a final follow-up four weeks after the end of treatment.
Safety was assessed through several measurements, including vital signs, electroencephalograms, seizure frequency, and suicidal thoughts, which were all found to be in normal ranges and without meaningful changes in the treatment group.
Participants on Epidiolex had more adverse events than those in the placebo group, but the treatment was generally well-tolerated at all three doses tested. The most common adverse events associated with Epidiolex, occurring in three or more patients, were fever, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior.
Six children treated with both Epidiolex and valproate had elevated transaminases — enzymes that can indicate liver damage — but none met the criteria for drug-induced liver injury and all six recovered.
No interactions were observed between Epidiolex and other anti-epileptic drugs also being taken by patients, except for an increase in N-desmethylclobazam levels, a byproduct of clobazam. This interaction did not occur in patients who were also on stiripentol, likely due to its inhibitory effect on the liver enzyme CYP2C19, but additional studies on drug distribution and drug-drug interactions are needed.
Since all three doses of Epidiolex were generally well-tolerated in Part A, researchers chose 20 mg/kg/day as the appropriate dose for Part B, which was a Phase 3 randomized trial.
During this part, the effectiveness of Epidiolex as an add-on therapy to anti-epileptic treatment was evaluated. Subjects received the investigational product for 14 weeks, including a dose-escalating period, followed by a 12-week maintenance period, during which the frequency of monthly convulsive seizures was measured.
Results from this part of the CARE1 trial (NCT02091375), previously published in the New England Journal of Medicine, demonstrated that a daily dose of 20 mg/kg in addition to standard anti-epileptic treatment over 14 weeks led to a 39% decrease in patient seizure frequency, compared with 13% in the placebo group.
Epidiolex is also currently being tested by GW in other Phase 3 trials for severe and treatment-resistant epilepsy syndromes including Dravet and Lennox-Gastaut syndrome.
GW has launched a Phase 3 trial, CARE2 (NCT02224703), investigating the safety and effectiveness of Epidiolex in children and young adults with Dravet syndrome. The randomized trial is currently recruiting up to 150 participants ages 2 to 18 at multiple centers in the United States and Europe.
Treatment with Epidiolex also recently showed promising results in a Phase 3 trial for Lennox-Gastaut syndrome (NCT02224690). Compared with patients receiving placebo, those on Epidiolex had a stronger reduction in monthly drop seizures — 22% versus 44%, respectively. Reductions in drop seizures were observed in the first month of Epidiolex treatment and maintained thereafter.
Epidiolex was granted orphan drug status by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency. The FDA also recently accepted for review a new drug application (NDA) for the therapy.