The purified oral formulation of cannabidiol (CBD; Epidiolex, GW Pharmaceuticals) reduced seizure frequency by 39% in children with Dravet syndrome in the first large-scale randomized, double-blind, placebo-controlled clinical trial.
“It’s a landmark study in many ways,” lead investigator, Orrin Devinsky, MD, director of the Comprehensive Epilepsy Center at NYU Langone Medical Center in New York City, told Medscape Medical News.
“People have been prescribing cannabis products for epilepsy for 4000 years from historical records, and for the first time we actually have scientific evidence that a compound from cannabis works,” said Dr Devinsky.
“The most important finding is that cannabidiol, which is the major nonpsychoactive component in cannabis, is both effective and well tolerated by the majority of patients with Dravet syndrome, which is one of the more severe childhood forms of epilepsy,” he added.
The study was published online May 24 in the New England Journal of Medicine.
“Very Striking” 5% Seizure-Free With CBD
The study, conducted at 23 sites in the United States and Europe, enrolled 120 children and young adults aged 2 to 18 years with Dravet syndrome and drug-resistant seizures.
They were randomly allocated to CBD, 20 mg/kg body weight per day (n = 61), or placebo (n = 59) on top of standard antiepileptic therapy for 14 weeks. The primary endpoint was change in convulsive-seizure frequency over the 14-week treatment period, relative to a 4-week baseline period.
Seizure frequency dropped in the CBD group by 39%, from a median of 12.4 per month before treatment to 5.9 with CBD treatment, compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the CBD group and the placebo group in change in seizure frequency, –22.8 percentage points; 95% confidence interval [CI], –41.1 to –5.4 percentage points; P = .01).
In addition, 43% of patients receiving CBD had at least a 50% reduction in convulsive-seizure frequency vs 27% of patients receiving placebo (odds ratio, 2.00; 95% CI, 0.93 – 4.30; P = .08).
The frequency of total seizures of all types was also significantly reduced with CBD (P = .03), but there was no significant reduction in nonconvulsive seizures.
“A very striking 5% of patients in the treatment group were seizure free on the cannabidiol, which is fantastic,” Dr Devinsky told Medscape Medical News. “These were kids on 3 or 4 drugs. Many of them had failed 10 drugs in the past and had never been seizure free for more than a week, and some of these kids were seizure free for all 14 weeks of the trial.”
The patients’ overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the CBD group vs 34% of the placebo group (P = .02).
Side effects that emerged during the treatment period were reported by 93% of patients in the CBD group and 75% of those in the placebo group and were generally mild or moderate in severity.
Common side effects in the CBD group (>10% frequency) were vomiting (15%), diarrhea (31%), fatigue (20%), pyrexia (15%), upper respiratory tract infection (11%), decreased appetite (28%), convulsion (11%), lethargy (13%), and somnolence (36%).
Eight patients in the CBD group withdrew from the trial because of side effects compared with one patient in the placebo group.
Some effects of CBD may relate to interactions with other antiepileptic drugs, the researchers say. “Abnormalities of hepatic aminotransferase levels occurred only in patients taking valproate, suggesting an interaction in which cannabidiol may potentiate a valproic acid-induced change in hepatic aminotransferase levels,” they report.
“Compared to drugs that are approved by the FDA, I think the side effect profile was quite favorable,” Dr Devinsky said. “I am very positive and excited about the results of this study, but I think it’s important that people recognize that this is not a panacea. Many children did not benefit from the drug, and some had side effects that were troublesome.”
The results of this study confirm results from an open-label expanded-access treatment program with the CBD Epidiolex led by Dr Devinsky and published in 2015, as reported by Medscape Medical News.
“Hot-Button” Issue
In an editorial published with the new study, Samuel Berkovic, MD, from the Epilepsy Research Centre, University of Melbourne at Austin Health, Heidelberg, Victoria, Australia, notes that medicinal cannabis is a “hot-button issue in the treatment of epilepsy. The issue of its use is frequently raised in medical consultations, in the lay press, in social media, and at scientific meetings where the lack of hard data is disheartening.”
Therefore, writes Dr Berkovic, this “well-performed double-blind, controlled trial of Devinsky et al. in this issue of the Journal showing the effectiveness of cannabidiol in the Dravet syndrome is welcome.”
This trial “represents the beginning of solid evidence for the use of cannabinoids in epilepsy,” and it needs replication, Dr Berkovic says.
“Future trials may answer further questions about the applicability of cannabinoids to the many other syndromes of childhood epilepsy and to treatment in adults. After an era dominated by anecdote and obfuscated by medicolegal issues and emotionally infused debate, more scientific studies are under way. Much more research is needed to understand the basic science, benefits, and risks of cannabinoids in epilepsy,” Dr Berkovic concludes.
Dr Devinsky noted that topline results from two trials of this CBD product in Lennox-Gastaut syndrome, another severe form of epilepsy, also look promising.
“I would say it looks very encouraging that this will work for at least some other types of epilepsy. Dravet and Lennox-Gastaut syndrome probably account for no more than 1% of all epilepsy, so the question is going to be, what about the other 99% of people with epilepsy — How well does cannabidiol work for them? We don’t have an answer right now,” Dr Devinsky noted.
Epidiolex has not been approved by the US Food and Drug Administration (FDA). In a statement, the company said the new drug application for this product remains on track for submission to the FDA in the middle of 2017.
GW Pharmaceuticals funded the study. Dr Devinsky reports receiving grant support from Novartis, PTC Therapeutics, and Zogenix and holding equity interest in Rettco, Pairnomix, Tilray, and Egg Rock Holdings. A complete list of author disclosures is listed with the original article.
N Engl J Med. Published online May 24, 2017. Abstract, Editorial
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