Epidiolex's Anti-Seizure Activity in LGS Not Affected by Taking Clobazam

When given as an add-on therapy, Epidiolex (cannabidiol, CBD) can lower the frequency of seizures in young patients with Dravet and Lennox‐Gastaut syndromes — regardless of whether the children also are taking clobazam — a review has found.

These findings suggest that Epidiolex may have its own anti-epileptic properties, and contradict current theories that its benefits are due only to its ability to increase clobazam’s availability in the body, according to the researchers. Those current theories have restricted the therapy from being prescribed in Europe, they noted.

The review study, “Cannabidiol efficacy and clobazam status: A systematic review and meta-analysis,” was published in the journal Epilepsia.

Epidiolex, marketed by Greenwich Biosciences, a subsidiary of GW Pharmaceuticals, is an oral cannabidiol solution derived from the cannabis plant. It has strong anti-seizure, anti-psychotic, and anti-anxiety (anxiolytic) properties.

Previous clinical trials demonstrated that Epidiolex was able to safely and effectively lower the frequency of seizures in children with Lennox-Gastaut and Dravet syndromes, two drug-resistant forms of epilepsy.

These findings have supported Epidiolex’s approval in the U.S. and Europe as an anti-seizure therapy to treat patients with Dravet and LGS, ages 2 and older. More recently, the U.S. Food and Drug Administration announced it had approved an expansion of the therapy’s original label indication that allows infants, ages 1 and older, to have access to the medication.

However, the discovery of drug-drug interactions between Epidiolex and clobazam — sold under the brand name Onfi and Sympazan in the U.S., and as Frisium and Tapclob, among others, in Europe — “raised questions regarding the intrinsic antiseizure activity of [Epidiolex] and have imposed prescription limits in Europe,” the researchers wrote.

Thus far, findings from clinical studies that have attempted to determine the consequences of these drug-drug interactions also have been inconsistent.

Now, an international group of researchers set out to evaluate the impact of clobazam co-administration on Epidiolex’s effectiveness in patients with Dravet and LGS. To do so, the team systematically reviewed published data from randomized, placebo-controlled trials.

The researchers used three online databases — Pubmed, CENTRAL, and the U.S. Clinical Trial Registry — to search for trials assessing the efficacy of Epidiolex in young patients with LGS or Dravet.Four multi-center, Phase 3 trials, covering 714 participants — 429 receiving Epidiolex and 285 a placebo — were included in the meta-analysis. These were: GWPCARE1 (NCT02091375), GWPCARE2 (NCT02224703), GWPCARE3 (NCT02224560), and GWPCARE4 (NCT02224690).The patients’ ages ranged from about 9 to 15. Epidiolex was given twice a day at a total daily dose of 10 or 20 mg/kg.From those who were on Epidiolex, 240 (55.9%) also were taking clobazam, while the remaining 189 (44.1%) were not receiving the therapy. Among those who were being treated with a matched placebo, 158 (55.4%) also were taking clobazam and 127 (44.6%) were off the medication.

The results showed that a significantly greater proportion of patients treated with Epidiolex achieved at least a 50% drop in seizure frequency, compared with those on a placebo. This was true both for patients not on clobazam (29.1% vs. 15.7% in the placebo group) and for those being co-treated with clobazam (52.9% vs. 27.8%).

Patients who were not being co-treated with clobazam showed lower response rates, both on Epidiolex and on the placebo. The researchers hypothesize that these individuals may be particularly difficult to treat, as they had failed more anti-seizure medications, including clobazam, and had higher seizure frequency at enrollment.

“This analysis suggests [Epidiolex] to have independent antiseizure activity and efficacy irrespective of [clobazam] administration and cannot support the current prescription restriction [in Europe],” the researchers wrote.

Nevertheless, they noted these findings should be interpreted with caution, due to the limited number of patients participating in these trials, and to the fact that treatment with clobazam was not given randomly in any of the studies included in the final meta-analyses.

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