Epidiolex-associated reduction in the frequency of drop seizures may be caused by an interaction between its active component — cannabidiol (CBD) — and clobazam, a well-known anti-seizure medication, according to a recent study.
This may explain the European Commission’s recent approval of Epidyolex (its European brand name) as an add-on therapy to clobazam for treating seizures associated with Lennox‑Gastaut syndrome (LGS) and Dravet syndrome, another type of severe childhood epilepsy.
It also could have important implications on Epidiolex’s use and approved indication for the same patient population in the U.S., where it is currently available as an independent adjuvant (secondary) therapy.
CBD, the major non-psychoactive cannabinoid (active component) in the cannabis plant, acts on the body’s endocannabinoid system — a complex modulatory network involved in brain development, memory, movement control, hormone production, and immune reactions.
Increasing evidence suggests that CBD has numerous beneficial properties, including anti-seizure, anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory.
GW Pharmaceuticals‘ Epidiolex, a purified oral form of CBD, was the first cannabis-based medicine to be approved in the U.S., and more recently, in Europe, for the treatment of seizures associated with LGS and Dravet syndrome in patients two years and older.
Distinct from its independent indication in the U.S., Epidiolex’s European approval was limited to a combination with the anti-seizure medication clobazam — marketed as Onfi and Sympazan in the U.S. and under the brand names Frisium and Tapclob, among others, in Europe. Several studies have shown that clobazam effectively reduces drop-seizure frequency in people with LGS.
Now, data from a recent study may explain the reasons behind the more recent clobazam-dependent indication for Epidiolex in Europe.
The therapy’s approval by both regulatory agencies was based on positive data from three Phase 3 trials (NCT02091375, NCT02224703, and NCT02224560) and an open-label extension study (NCT02224573), evaluating Epidiolex in patients with LGS or Dravet syndrome.
Results of the two LGS trials showed that daily 20 mg/kg of Epidiolex reduced the drop-seizure frequency by about 40%, which was more than twofold of that seen in patients receiving a placebo.
Despite these promising results, CBD’s exact mechanism of action and how it interacts with other anti-seizure treatments is only starting to be explored.
Previous studies evaluating the interaction of Epidiolex with other anti-epileptic therapies showed that the combination of Epidiolex and clobazam resulted in a bidirectional interaction between the two compounds, increasing the levels of their active components in the blood of healthy people.
Epidiolex (20 mg/kg per day) was further shown to increase the levels of clobazam’s active component (as its degradation is suppressed by cannabinoids) by an average of threefold to sixfold in people with or without epilepsy.
Since about half of LGS patients in Epidiolex’s clinical trials also were taking clobazam, researchers in The Netherlands set out to clarify whether Epidiolex’s effects could be attributed to its interaction with clobazam.
To evaluate this theory, they conducted several clinical trial simulations based on data of the GWPCARE3 study (NCT02224560) — which evaluated Epidiolex (20 mg/kg/day) in children and adults with LGS — and an assumption that patients on clobazam would have an Epidiolex-dependent increase in clobazam’s active component levels.
These computer-based simulations use mathematical models, based on a medicine’s detailed information, to test hypotheses, help design new trials, and identify ways to improve a medicine’s effectiveness.
The simulations resulted in similar reductions in seizure rates as the real clinical data, suggesting that “the reduction in drop-seizure frequency observed in the cannabidiol groups is likely to be largely explained by a drug-drug interaction with clobazam,” the researchers wrote.
“The effects of cannabidiol on seizure frequency in Lennox-Gastaut patients could be explained entirely through estimated elevations of blood levels of clobazam, which might mean that cannabidiol in itself may not have any, or at best limited, anti-epileptic effects,” Geert Jan Groeneveld, MD, PhD, the study’s senior author, said in a press release.
“This may have important implications for the use of [Epidiolex] and its FDA registration,” the researchers wrote.
Based on these data, the team hypothesized that this interaction also might explain the positive results of Epidiolex in people with Dravet syndrome, considering that 60% of these patients were receiving clobazam during the Dravet clinical trial.
Researchers noted, however, that their simulations had some limitations, and that the public availability of all data of the CBD trials in LGS would enable their conclusions to be strengthened or rejected.