Growing Evidence for Cannabidiol to Treat Lennox Gastaut Syndrome and Dravet Syndrome
Results of a phase 3 clinical trial comparing adjunctive treatment with cannabidiol (CBD) (Epidiolex; GW Pharmaceuticals/Greenwich Biosciences, Carlsbad, CA) to placebo showed that adding oral CBD to treatment of patients with refractory Lennox-Gastaut syndrome significantly reduced the frequency of drop seizures by as much as 41.9% compared to a 17.2% drop achieved with placebo (P = .005). (N Engl J Med 2018; 378:1888-1897.)
The oral CBD produced by GW Pharmaceutical/Greenwich Biosciences is very carefully manufactured in a controlled, standardized way to produce a medicine that physicians and patients can be assured is the same every single time a dose is delivered. It is pharmaceutical-grade formulation of highly purified CBD, which does not produce the cognitive effects, or high, associated with medical marijuana and other cannabis products. Importantly, this formulation is made under rigorous drug safety standards, and the effects of this compound cannot be extrapolated to other noncontrolled products, particularly other cannabinoid oils of unknown composition and dose. Information to help differentiate FDA-approved cannabis derivatives and those in clinical trials from medical marijuana is available at www.cannabinoidclinical.com.
The study randomized 225 patients with refractory LGS to 1 of 3 groups: CBD oral solution (10 mg/kg/d, n = 73 or 20 mg/kg/day, n = 76) or placebo (n = 76). Participant’s mean age was 16 years and subjects had previously tried and discontinued an average of 6 other antiepileptic drugs (AEDs) and were currently taking an average of 3 AEDs to which the cannabidiol or placebo were added. The baseline seizure frequency was measured for 4 weeks prior to a 14-week treatment, which included an initial 2-week dose escalation period.
Sensitivity analyses confirmed that the treatment effect of CBD was established during the first month of treatment (post-titration) and sustained over the entire treatment period. Patients taking CBD had a 41.9% (20 mg/kg/day, P = .005) or 37.2% decrease (P = .002) in seizure frequency compared to a 17.2% decrease for those who were given placebo. Patients and caregivers for those treated with CBD reported more improvement on subjective impression of change questionnaires compared to placebo (P < .05 for both doses).
Results for the use of CBD oral solution to treat seizures associated with Dravet syndrome have been previously reported (N Engl J Med 2017; 376:2011-2020.), with patients taking 20 mg per kg per day experiencing a 39% drop in seizure frequency compared to a 13% drop experienced by those taking placebo.
CBD oral solution has been generally well tolerated in both trials, and adverse effects of note included somnolence, decreased appetite, diarrhea, upper respiratory infection, pyrexia, vomiting, and nasopharyngitis. Although status epilepticus occurred, it was not deemed treatment related. Elevation of liver transaminase but not bilirubin levels sometimes occurred, most commonly in patients taking the higher dose and valproate and was dose-related and reversible. Several ongoing safety study results were presented at the 2018 American Academy of Neurology (AAN) meeting and showed similar safety results over longer periods. CBD has also been shown to have lower potential for abuse than other schedule III and IV drugs.
Timetable for Approval
A New Drug Application (NDA) for use of CBD oral solution to treat seizures associated with LGS and Dravet syndrome was accepted by the Food and Drug Administration (FDA) for priority review in December 2017, and unanimously recommended for approval by the Peripheral and Central Nervous System Drugs Advisory Committee of the FDA, and a goal date for FDA decision of June 27, 2018 has been set. If approved, CBD is expected to be available by prescription in the second half of 2018.
If approved, CBD will be the first drug approved for treatment of seizures associated with Dravet syndrome. It will also be the first FDA-approved formulation of cannabidiol and the first prescription medicine derived from the cannabis plant. Cannabis-derived medicines are also being studied to treat other refractory epilepsies, communication and behavioral difficulties of people with autism, and potential uses for helping persons with intellectual disabilities, spasticity associated with multiple sclerosis, and cancer.
Justin Gover, GW’s Chief Executive Officer stated, “We are passionate believers in the potential of cannabinoids to be a source of a range of novel prescription medicines. The evidence for efficacy and safety of Epidiolex in treating LGS and Dravet syndrome supports that. We look forward to a decision from the FDA in late June.”
"Positive study results, such as these, offer much needed hope for patients and their families living with this debilitating condition," said Christina San Inocencio, Executive Director of the Lennox-Gastaut Syndrome Foundation. "New options are desperately needed and the LGS community is very excited about the potential of cannabidiol as a new, differentiated treatment option for patients for whom current treatments have failed to provide adequate benefit.”