BOSTON – Cannabidiol add-on treatment significantly reduces the frequency of drop seizures in patients with Lennox-Gastaut syndrome, according to findings from the randomized, double-blind, placebo-controlled GWPCARE4 and GWPCARE3 trials.
In GWPCARE4 – the first controlled trial of cannabidiol in Lennox-Gastaut syndrome (LGS) – 171 patients were randomized to receive either placebo or cannabidiol oral solution at a dose of 20 mg/kg per day for 14 weeks, including 2 weeks of titration and 12 weeks of maintenance therapy. The drop seizure frequency decreased by a median of 44% in the cannabidiol group vs. 22% in the placebo group. The difference between the groups was statistically significant and was apparent within the first 4 weeks of the maintenance period, Jacqueline French, MD, director of translational research and clinical trials in epilepsy at New York University Langone Medical Center reported at the annual meeting of the American Academy of Neurology.
Study participants had a mean age of 15 years, and 34% were aged 18 years or older. The median drop seizure frequency was 74 per month at baseline.
“That is a very high seizure burden,” Dr. French said, noting that the median total drop and non-drop seizure frequency was in the mid to high 100s. “So you can see that these children were very afflicted by seizures.”
Interestingly, there was a “very substantial drop” in non-drop seizures, as well, she said.
“And that’s really hard to demonstrate, so that’s impressive to me, at least,” she added.
Patients had taken a median of six antiepileptic drugs (AEDs) in their past and were taking a median of three AEDs in addition to the cannabidiol throughout the study period.
Adverse events were common, occurring in 86% of cannabidiol patients and 69% of placebo patients. The most common were diarrhea, somnolence, pyrexia, decreased appetite, and vomiting, but most were mild or moderate. Treatment-related serious adverse events were reported in nine cannabidiol patients and one placebo patient. All patients who completed the trial entered an open-label extension study, Dr. French said.
GWPCARE4 was followed by GWPCARE3, which compared both 20 mg/kg per day and 10 mg/kg per day doses of cannabidiol with placebo.
In that study, 225 patients with a mean age of 16 years (30% were aged 18 years or older) were randomized, and the median drop in seizure frequency was 42% with 20 mg/kg of cannabidiol and 37% with 10 mg/kg of cannabidiol versus 17% with placebo, Anup D. Patel, MD, reported at the meeting.
Approximately 40% and 36% of patients in the 20 mg/kg and 10 mg/kg groups, respectively, achieved the secondary outcome of a 50% or greater drop in seizure frequency, compared with 15% of placebo patients.
“Overall, 5 patients in the 20 mg/kg per day arm, 3 in the 10 [mg/kg per day arm], and 1 in the placebo arm achieved drop seizure freedom during the maintenance period of our study,” said Dr. Patel, a pediatric neurologist at Nationwide Children’s Hospital, Columbus, Ohio.
The median monthly drop seizure frequency at baseline was 80-87 in the three groups, and patients had previously failed a median of six to seven AEDs. They took a median of three AEDs during the study.
Adverse events occurred in 94% of patients in the 20-mg/kg cannabidiol group, 84% of those in the 10-mg/kg group, and 72% of placebo patients, and most were mild or moderate. The most common were somnolence and decreased appetite.
Treatment-related serious adverse events were reported in 5, 2, and 0 patients in the groups, respectively. Some elevations in transaminases were seen (in 11 patients in the 20-mg/kg dose group, and 2 in the 10-mg/kg dose group), but no patients met criteria for drug-induced liver injury with concurrent elevated bilirubin, and all cases resolved, Dr. Patel said.
Similar findings were noted in GWPCARE4, and both Dr. Patel and Dr. French noted that most patients with elevated transaminases were also taking valproic acid.
No deaths occurred in either GWPCARE4 or GWPCARE3.
“We feel both doses... produce significantly greater reductions in drop seizures as compared to placebo,” Dr. Patel said.
In an interview, he noted that the two cannabidiol doses were not compared directly to determine if the differences in response rates and adverse events were statistically significant, but said that the rates appeared comparable, and that the adverse event rates were high in all of the groups, reflecting a very sick patient population.
Of the 212 patients who completed GWPCARE3, 99% entered an open-label extension study.
Eligible patients in both trials were children and adults aged 2-55 years with a clinical diagnosis of LGS, at least two drop seizures (including tonic, atonic, and tonic-clonic seizures) each week at baseline, and documented failures on at least one AED.
Patients and caregivers in both trials were more likely to report improvement in overall condition among treated vs. placebo patients, as measured using the Subject/Caregiver Global Impression of Change scale.
The findings provide class 1 evidence that cannabidiol as add-on therapy in LGS is efficacious for reducing seizure frequency, and is generally well tolerated, Dr. French and Dr. Patel said.
Dr. French noted that enthusiasm for the trials was high, with many study sites reporting waiting lists for patient enrollment.
Some of the authors in each study have consulted for, conducted studies funded by, or received honoraria from GW Pharmaceuticals, which funded the GWPCARE4 and GWPCARE3 trials and manufacturers the oral cannabidiol solution. Several authors in each study were employees of GW Pharmaceuticals.