Pharmaceutical-grade cannabidiol (Epidiolex) as adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome received positive words from FDA staff in issued in advance of an that will be held Thursday.
The risk-benefit profile established by three clinical trials in LGS and Dravet syndrome "appears to support approval," they wrote. The trials demonstrated clinically meaningful and statistically significant reductions in seizure frequency and their results "provide substantial evidence" of cannabidiol's effectiveness in treating LGS and Dravet syndrome seizures, according to the review.
In light of this, possible risks associated with cannabidiol appeared acceptable: "Although the risk of liver injury has the potential to be serious, the observed risk can be appropriately managed with inclusion of relevant language in labeling, education of prescribers regarding the risk of transaminase elevation and need for monitoring of liver enzyme levels, and further characterization of the risk in the post-market setting," the document said.
The FDA is expected to decide on by June 27. The product would be the first cannabis-derived drug approved in the U.S.
LGS and Dravet syndrome are rare, severe, refractory epilepsy syndromes that emerge early in childhood. Both are linked to higher rates of mortality, primarily due to status epilepticus and sudden unexpected death in epilepsy patients (SUDEP). Cannabidiol, a cannabinoid prepared from marijuana, is structurally unrelated to other anti-seizure medications and currently is a Schedule I drug. Its anticonvulsant mechanism is unknown but does not appear to involve cannabinoid receptors.
Thursday's session of the Peripheral and Central Nervous System Drugs Advisory Committee will vote on only one question: whether the benefit-risk profile of the cannabis derivative is favorable for the treatment of seizures associated with LGS and Dravet syndrome in people 2 years old and older.
The application and safety data for cannabidiol came largely from two pivotal 14-week, multicenter, randomized, double-blind, placebo-controlled trials in patients with LGS, and one similar study of Dravet syndrome patients.
In both LGS studies, patients treated with cannabidiol showed significantly greater reductions in drop seizures -- the primary endpoint -- than placebo groups. Cannabidiol also produced greater median reduction in seizure frequency and higher overall improvement on the Subject/Caregiver Global Impression of Change (S/CGIC) scale.
In the Dravet syndrome trial, children who received cannabidiol had significantly greater reductions in the primary endpoint of convulsive seizures than placebo-treated patients. More patients on cannabidiol had at least a 50% reduction in convulsive seizures compared with those on placebo. Caregivers of Dravet patients also were more likely to report overall improvement on the CGIC scale.
Because LGS and Dravet syndrome patients are similar and because study designs and treatment doses were comparable, the FDA agreed to allow safety data to be pooled. An open-label extension trial and an expanded access program of patients with uncontrolled seizures provided supporting safety information.
Cannabidiol is known to interact with multiple epilepsy drugs and has been linked to raised liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT), notably with concomitant valproate (Depakote). A detailed evaluation of potential drug-induced liver injury accompanied the briefing document, as did a memorandum from the FDA controlled substances staff concluding that cannabidiol has negligible abuse potential.
The FDA is not obliged to follow advisory committee recommendations but it usually does.