In patients with Dravet syndrome who had discontinued an average of 4 antiepileptics drugs, while taking a mean of 3, cannabidiol reduced the incidence of seizures almost in half in doses of both 10 mg/kg and 20 mg/kg per day.
Ian Miller, MD
has been shown to cut seizure occurrence by almost 50% in patients with Dravet syndrome in doses of 10 mg/kg per day and 20 mg/kg per day, based on the results of a phase 3 study of the cannabis-derived medicine.1
All told, in 199 children who were taking an average of 3 antiepileptics drugs (AEDs) and had discontinued a mean of 4 prior, the total seizure reduction observed was 47% and 56% with the 20 mg/kg and 10 mg/kg doses of CBD, respectively, compared to a reduction of 30% with placebo (10 mg/kg, P
= .0255; 20 mg/kg, P
"It's exciting to be able to offer another alternative for children with this debilitating form of epilepsy and their families," study author Ian Miller, MD, director, Epilepsy and Neurophysiology Program, Nicklaus Children's Hospital, 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."
The full findings will be presented at the 2019 American Academy of Neurology (AAN) Annual Meeting in Philadelphia, Pennsylvania, May 4-10, 2019.
CBD was approved by the FDA for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome for patients 2 years of age and older in June 2018, under the trade name Epidiolex, and manufactured by GW Pharmaceuticals).3
Three months later, it was rescheduled by the Drug Enforcement Administration (DEA) to a Schedule V drug.4
In this study, dubbed GWPCARE2 (NCT02224703), the cohort was randomized 1:1:1 to either the 10 mg/kg (n = 67) or 20 mg/kg doses (n = 67), or placebo (n = 65). Patients were a mean age of 9 years, and the treatment period was 14 weeks.
The treatment groups experienced ≥50% responder rates of 49% and 44% for the 10 and 20 mg/kg dose groups, respectively, greater than the 26% for placebo (10 mg/kg, P
= .0069; 20 mg/kg, P
= .0332). Convulsive seizures were reduced by 46% and 49%, respectively, compared to a 27% reduction with placebo (10 mg/kg, P
= .0299; 20 mg/kg, P
As for safety, the incidence of adverse events (AEs) was similar across all groups, with incidence rates of 90% and 88% for the 20 and 10 mg/kg groups and 89% with placebo. "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 explained.
The 5 most common AEs were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Serious AEs were reported in 25% of those in the 20 mg/kg group, 20% of those in the 10 mg/kg group, and 15% of placebo patients. Only 7% of those in the 20 mg/kg group discontinued due to AEs. There were no deaths.
Elevated transaminases exceeding 3 times the upper limit of normal (ULN) occurred in 19% and 5% of patients in the 20 mg/kg and 10 mg/kg groups, respectively; no patient had elevations in bilirubin. Every patient was on concomitant valproate, and all elevations resolved.
A number of trials of CBD in rare epilepsies have been undertaken. In a separate study in Dravet syndrome, the median frequency of convulsive seizures per month declined by -6.5 from 12.4 at baseline for patients treated with cannabidiol. In the placebo group, seizures declined by just 0.8 from baseline. There were 43% of patients achieving a 50% reduction with cannabidiol compared with 27% with placebo (OR, 2.00; P
Recently, 3 experts—Daniel Friedman, MD, and Jacqueline A. French, MD, from NYU Langone; and Mauro Maccarrone, PhD, from the University of Rome—noted that based on the current clinical evidence, some cannabinoids such as CBD may provide some efficacy while remaining safe in neurological disorders such as epilepsy and multiple sclerosis (MS), though it remains to be seen for other conditions.6
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1. Cannabis-based Medicine May Reduce Seizures for Children with Difficult-to-Treat Epilepsy [press release]. Philadelphia, PA: AAN; Published April 30, 2019. prnewswire.com/news-releases/cannabis-based-medicine-may-reduce-seizures-for-children-with-difficult-to-treat-epilepsy-300841365.html. Accessed May 3, 2019.
2. Miller I, Perry MS, Saneto RP, et al. Cannabidiol (CBD; 10 and 20mg/kg/day) significantly reduces convulsive seizure frequency in children and adolescents with Dravet syndrome (DS): Results of a dose-ranging, multi-center, randomized, double-blind, placebo-controlled trial (GWPCARE2) Presented at: 2019 American Academy of Neurology Annual Meeting. May 4-10, 2019; Philadelphia, PA.
3. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy [press release]. Silver Spring, MD: FDA; Published June 26, 2018. fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms. Accessed May 3, 2019.
4. GW Pharmaceuticals plc and its U.S. Subsidiary Greenwich Biosciences Announce the DEA has Rescheduled EPIDIOLEX® (cannabidiol) Oral Solution to Schedule V [press release]. London, UK; Carlsbad, CA: GW Pharma. Published September 27, 2018. http://ir.gwpharm.com/news-releases/news-release-details/gw-pharmaceuticals-plc-and-its-us-subsidiary-greenwich-0. Accessed May 3, 2019.
5. Friedman D, French JA, Maccarrone M. Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders. Lancet Neurol. Published online March 22, 2019. doi.org/10.1016/S1474-4422(19)30032-8.
6. Devinsky O, Cross JH, Laux L, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017; 376:2011-2020.