“Is the benefit-risk profile of cannabidiol favorable for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients 2 years of age or older?”
This was the question posed to an FDA advisory committee on Thursday, April 19, 2018 regarding GW Pharmaceuticals’ Epidiolex (cannabidiol), and the committee voted a resounding “yes”. Committee members unanimously agreed (13-0) that Epidiolex demonstrated robust efficacy and a manageable safety profile in Phase III trials. One voting member called the decision a “no brainer”, while another declared that Epidiolex is “clearly a breakthrough drug for an awful disease.” The FDA itself had come to the same conclusion independently: during the opening remarks, Dr. Billy Dunn, the Director of the FDA’s Division of Neurology Products, stated that that the agency had nearly completed the review process and had “not identified any obstacles to approval.”
This is great news for the epilepsy community: Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are rare and debilitating epilepsy disorders that are typically diagnosed in childhood, often lead to developmental delays, and are associated with a high mortality rate. Dozens of antiepileptic drugs (AEDs) are marketed in the United States (though very few are approved specifically for LGS and DS), but the vast majority of LGS and DS patients continue to experience seizures despite treatment with multiple AEDs. To put this in perspective, LGS and DS patients recruited for the Phase III Epidiolex trials experienced a median of approximately 80 drop seizures or 15 convulsive seizures per month, respectively; these are the primary—and most disabling—seizure type in each syndrome. This was despite the fact that these patients had already failed to find relief on a median of 4-6 AEDs and were taking 3 AEDs at the time of enrollment.1
Just how safe and effective was Epidiolex in these patients? Efficacy data from the Phase III studies demonstrated that Epidiolex is effective in reducing the primary seizure type associated with LGS and DS by around 40% (vs. around 20% for placebo). Although very few patients attained true seizure freedom, testimonials from parents during the meeting emphasized that any decrease in seizure frequency can deliver meaningful gains in quality of life for these patients. In terms of tolerability, Epidiolex was associated with a number of side effects, including somnolence, decreased appetite, diarrhea, and fatigue, which were mostly mild or moderate in severity1; however, caregivers and physicians who spoke during the meeting reported that Epidiolex’s side-effect profile appears similar to or better than that of other AEDs.
Two important safety concerns were addressed in detail during the meeting. First, a safety signal for potential drug-induced liver damage (as measured by increased transaminase levels) arose during the clinical trials. However, practicing neurologists testified that this risk is manageable and that monitoring these levels is already routine for most epilepsy patients. Moreover, GW representatives noted—and FDA representatives confirmed—that transaminase levels returned to baseline within weeks for most Epidiolex-treated patients, even if Epidiolex wasn’t discontinued. Second was the risk of abuse. According to the DEA, cannabidiol is a Schedule I drug, meaning that it is considered to have “no currently accepted medical use and a high potential for abuse.”2 GW conducted an extensive set of studies demonstrating a low abuse potential with Epidiolex, and GW’s clinical program demonstrates that Epidiolex is medically useful in reducing seizures. To quote Katherine Bonson, Ph.D., of the FDA’s Controlled Substance Staff, “there is little evidence that Epidiolex has meaningful abuse potential, even at supratherapeutic doses in adults,” thereby suggesting that a Schedule 1 rating is, by definition, inappropriate.
The PDUFA data for Epidiolex is June 27th, and the results of this advisory committee meeting affirms our belief that the FDA will approve Epidiolex for the treatment of seizures associated with LGS and DS. The next step will be DEA scheduling, which usually occurs within three months after FDA approval; as such, Epidiolex could be available to U.S. patients this year. We’ll be speaking with epilepsy experts in May to get reactions to the meeting, opinions on Epidiolex, and expectations for its use in clinical practice, and we will be posting here again as we hear more from the company, the FDA, and the DEA. Stay tuned!
Briefing Information for the April 19, 2018 Meeting of the Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee. FDA website. Accessed April 19, 2018
Drug Scheduling. DEA website. Accessed April 19, 2018. https://www.dea.gov/druginfo/ds.shtml