Both the 10- and 20-mg doses were associated with clinically relevant reductions in convulsive seizures with a favorable safety and tolerability profile.
Ian Miller, MD
Results from the GWPCARE2 trial of 10 mg and 20 mg doses of adjunctive cannabidiol (CBD, Epidiolex; GW Pharmaceuticals) demonstrated similar clinical reductions in convulsive seizure frequency in patients with Dravet syndrome (DS) compared to placebo, though a better safety and tolerability profile was observed for the 10 mg/kg/d dose.1
“Drug-resistant seizures are common with Dravet syndrome and it is valuable to have a range of approved doses that offer physicians the flexibility to adjust treatment to a patient’s specific needs,” Ian Miller, MD, chief of neurology at Nicklaus Children’s Hospital in Miami, Florida, said in a statement.2
CBD oral solution was originally approved for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and DS in patients 2 and older in June 2018. Additionally, the drug has been linked to improvements in nonseizure-related behavioral and quality of life measures in patients with LGS and DS.
More recently, GW Pharmaceuticals announced that it has submitted a supplemental new drug application (sNDA) for CBD oral solution for the treatment of seizures associated with tuberous sclerosis complex (TSC).
GWPCARE2 (NCT02224703) was a double-blind, placebo-controlled clinical study that included 199 patients aged 2 to 18 years with a confirmed diagnosis of DS. Notably, each patient included in the trial had at least 4 convulsive seizures during the 4-week baseline period while receiving at least 1 antiepileptic drug.
Over a 14-week treatment period, patients were randomized to either CBD oral solution 10 mg/kg/d, CBD 20 mg/kg/d, or placebo. Patients’ dosing was gradually escalated, with a starting dose of 2.5 mg/kg/d reaching the 10 mg/kg/d dose on day 7 and the 20 mg/kg/d dose on day 11.
The primary endpoint was change from baseline in convulsive seizure frequency during the treatment period. Change in Caregiver Global Impression of Change score, change in all seizure frequency, and proportion of patients with at least a 50% reduction in convulsive seizure activity were observed as secondary outcomes.
Overall, 66 of the 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 52.5% female)were randomized to CBD 10 mg/kg/d, 67 to CBD 20 mg/kg/d, and 65 to placebo. In total, 190 patients completed the treatment.
From baseline, patients in the 10 mg/kg/d and 20 mg/kg/d groups experienced a 48.7% and 45.7% reduction in convulsive seizure frequency, with a reduction s from placebo of 29.8% (95% CI, 8.4%-46.2%; P = .01) in the 10 mg group and 25.7% (95% CI, 2.9%-43.2%; P = .03) in the 20 mg group, respectively.
Of the 198 patients that participated in the study, treatment-emergent adverse events (TEAEs) occurred in 176 patients (88.9%). Researchers concluded that 162 of those TEAEs were mild or moderate in severity. Decrease appetite, diarrhea, somnolence, pyrexia, and fatigue were all among the most common AEs, recorded in at least 10% of patients.
Serious adverse events were recorded in 40 patients, and 5 patients in the CBD 20 mg/kg group discontinued treatment due to AEs. Notably, AEs were resolved in 61 of 118 patients in the CBD groups and 35 of 58 in the placebo group by the end of the trial.
“EPIDIOLEX continues to represent an important advancement in the treatment of difficult-to-treat pediatric-onset epilepsies such as Dravet syndrome where there are few FDA-approved therapies,” said Justin Gover, GW Pharmaceuticals chief executive officer, in a statement. “We are pleased that the full results of our GWPCARE2 study in Dravet syndrome are now available to the greater neurology community.”
1. Miller I, Scheffer IE, Gunning B. Dose-ranging effect of adjunctive oral cannabidiol vs placebo on convulsive seizure frequency in Dravet syndrome. JAMA Neurol. Published online March 2, 2020. doi:10.1001/jamaneurol.2020.0073
2. Epidiolex significantly reduced convulsive seizure frequency in children taking anti-epileptic drugs with poor seizure control [news release]. Carlsbad, CA: GW Pharmaceuticals. March 2, 2020. Accessed March 3, 2020. globenewswire.com/news-release/2020/03/02/1993656/0/en/JAMA-Neurology-Publishes-Results-from-Positive-Phase-3-Trial-of-EPIDIOLEX-cannabidiol-oral-solution-in-Children-with-Seizures-Associated-with-Dravet-Syndrome.html.