Epidiolex’s Anti-seizure Effect Called Into Question by New Study
The US Food and Drug Administration’s (FDA) 2018 decision to approve Epidiolex for the treatment of severe epileptic seizures has been called into question by a new a study published in the British Journal of Clinical Pharmacology.
The strawberry-flavored cannabidiol (CBD) solution was approved off the back of three randomized, double-blind, placebo-controlled clinical trials, which involved 516 patients with either Lennox-Gastaut or Dravet syndrome.
Now the authors of the new study claim that the reduction in seizures witnessed in the trials could be attributed to a drug more commonly used to treat epilepsy, clobazam, which was also given to many of the patients in the trials.
A second look
The FDA-cited clinical trials found that CBD could reduce the number of seizures by up to 40 percent in some children.
“I went back to [two of the three cited] papers… and I thought, ‘let’s have a look.’ How many of those patients were actually using clobazam?” said Geert Jan Groeneveld, the chief scientific officer at the Centre for Human Drug Research in the Netherlands, and lead author of the new study.
“And I was awestruck,” he told Analytical Cannabis. “I was flabbergasted when I saw that 50 percent in one study and 60 percent in the other study were actually using this other drug, clobazam.”
Clobazam is an anti-seizure medication approved to treat children with Lennox-Gastaut syndrome. All three of the FDA-cited studies provided clobazam to some of the participants to take “concomitantly” with CBD. Now Groeneveld and his colleagues are questioning whether CBD’s supposed anti-seizure effects could actually be due to the commonly used anti-seizure medication.
“I'm not saying that I know for a fact that cannabidiol does not have any anti-epileptic effects,” Groeneveld said. “What I am saying is, I can explain the effects that you've observed through elevated blood levels of clobazam.”
To reach their conclusions, Groeneveld and his colleagues partly replicated one of the three FDA-cited studies in a clinical trial simulation, on the assumption that clobazam levels were 10 to 20 mg per patient.
They found that the reduction in seizures attributed to CBD may be explained by a beneficial drug-to-drug interaction with clobazam; as CBD is known to boost the medicinal effect of clobazam, the combination of the two drugs could have benefited patients more than either drug could achieve individually.
“I can explain the effects that were observed through a drug-drug interaction,” Groeneveld clarified. “I do not need any anti-epileptic effects of cannabidiol to explain the observations.”
Over to the FDA
Groeneveld says that his study’s findings may have important implications for the use of CBD and its FDA registration.
“If you look at the registration dossier of clobazam, it already has all these studies looking at potential drug-to-drug interactions,” he said. “And what I find very interesting is that Epidiolex was approved without this proof that it's not due to a drug-to-drug interaction.”
“I know that the [FDA] know about this possibility. And I think they requested some additional studies to be performed.”
More than 15,000 patients have taken Epidiolex in the US since its launch last year. Its producer, GW Pharmaceuticals, earned $86.1 million in revenue from the drug in 2019’s first quarter.
“[If GW] haven't shared [the clobazam data] with the FDA, and Epidiolex has been approved in that case, I think it should lead to reassessing whether that was done correctly and whether Epidiolex should be approved for the treatment of epilepsy,” Groeneveld added, “because it might be due to a drug-to-drug interaction.”
Epidiolex was approved for use in Europe this September and endorsed by the National Health Service in England today.
A recent review from NHS England advocated that children’s experiences with medicinal cannabis should be considered as evidence of how well the drug works.
Cannabis’ potential as a treatment for epilepsy was central to the medical cannabis legalization movement in the United Kingdom last year. The high-profile cases of two young boys with severe forms of epilepsy, Alfie Dingley and Billy Caldwell, captured the attention and sympathies of the UK public.
“Our doctors were saying to us that he was so seriously ill that the seizures may kill him,” Hannah Deacon, Alfie Dingley’s mother and medical cannabis campaigner, explained to Analytical Cannabis in June.
“So we then went to Holland, where we worked with a pediatric neurologist to use medical cannabis, and we saw [Alfie’s] seizures drop to once every 17 days, and then one seizure every 40 days. So, for us, it was like a miracle.”
To further clarify cannabis' properties, the largest medical trial of its kind in Europe was launched last week. The two-year-long project will involve up to 20,000 patients and study cannabis' effect on epilepsy, chronic pain, multiple sclerosis, and several mental health disorders.
“I think [CBD] is a very interesting substance, so is THC – I do a lot of research into cannabinoids,” Groeneveld said. “But if you want to register it as a drug, it needs to be for the right reasons.”