Synthetic transdermal cannabidiol (ZYN002, Zygel) as an add-on treatment showed positive results in children with developmental and epileptic encephalopathies, the open-label phase II BELIEVE study showed.
Consciousness-impairing seizures were cut by a median of 44% at 3 months and 73% at 12 months from baseline with adjunctive cannabidiol (CBD) gel, reported Ingrid Scheffer, MBBS, PhD, of the University of Melbourne in Australia, and co-authors, at the American Epilepsy Society 2020 virtual annual meeting.
Pharmaceutical-grade CBD (Epidiolex) in oral solution is approved in the U.S. for certain developmental and epileptic encephalopathies, including Dravet and Lennox-Gastaut syndromes and tuberous sclerosis complex. But oral medications can be difficult to give if a patient has behavioral or cognitive impairments, Scheffer noted.
„There are alternative ways to administer CBD which may be more suitable for patients than oral administration,” she told MedPage Today. „It’s also important to perform trials of CBD across a broad range of epilepsies and etiologies.”
In earlier research, CBD gel failed to reduce seizure frequency versus placebo in adults with focal epilepsy. While this may have been due to the doses used in the study, „I think it is more likely related to the placebo arm of the adult study,” Scheffer said. „There was an unusually high response rate, which meant the active arm appeared ineffective.”
BELIEVE was a manufacturer-sponsored, two-center, multiple-dose study of CBD gel in patients 3 to 17 years old with developmental and epileptic encephalopathies. Patients took one to four antiseizure drugs in a stable regimen that was maintained throughout the study and had a history of regression, slowing, or plateau in at least one developmental domain after seizure onset.
Weight-based doses of cannabidiol gel were applied every 12 hours during a 26‐week treatment period, in twice daily doses of 125 mg (if patients were under 25 kg) or 250 mg (if they were over 25 kg). Doses could be titrated up to 375 mg or 500 mg twice a day, depending on patients’ weight. Patients had an option to continue for up to 46 more weeks in an extension study.
Of 48 participants enrolled and analyzed for safety, 46 were evaluated for efficacy in the 26‐week treatment period. Median age was 10 and 26 patients were boys. About 27% had Lennox-Gastaut or Dravet syndrome, 6% had West syndrome, and 66% had other developmental and epileptic encephalopathies. More than half (54%) had focal impaired awareness seizures; 44% had tonic-clonic seizures, including generalized tonic-clonic seizures and focal to bilateral tonic-clonic seizures.
Median reductions from baseline at 6 months for focal impaired awareness seizures were 45%; for generalized tonic-clonic seizures they were 60%, and for focal to bilateral tonic-clonic seizures, they were 59%. At 12 months, median reductions for focal impaired awareness seizures, generalized tonic-clonic seizures and focal to bilateral tonic-clonic seizures were 100%, 83%, and 59%, respectively. Exploratory analysis showed that participants who had co-existing autism also had fewer focal impaired awareness and tonic-clonic seizures from baseline.
Fourteen patients reported 30 serious adverse events over the 72-week treatment period. The researchers considered two events — lower respiratory tract infection and status epilepticus — as possibly drug related. Patients had no clinically significant changes in vital signs, ECGs, or laboratory findings, except one patient who had a transient, benign, isolated elevation of alkaline phosphatase at week 26 that was considered unrelated to CBD.
Questions have been raised about the long-term consequences of treating children with CBD, said Daniel Friedman, MD, of NYU Langone in New York City, who wasn’t involved with the study.
„While there are concerns about the neurodevelopmental effects of CBD in children, especially younger kids, we know that seizures can also have deleterious effects on cognition,” Friedman noted. „Therefore, it is likely the known benefits related to better seizure control may outweigh the theoretical risks,” he told MedPage Today.
„We have limited knowledge about neurodevelopmental risks for most marketed anti-seizure medications we use in infants and children,” he added.
Findings support further study of transdermal CBD in patients with developmental and epileptic encephalopathies, the researchers said. Drugmaker Zynerba Pharmaceuticals also is evaluating transdermal CBD for behavioral symptoms in children with Fragile X syndrome.
Disclosures
This research was funded by Zynerba Pharmaceuticals.
Scheffer has received research support and consulting fees from Zynerba.