Long-Term Efficacy for Epidiolex in Resistant Epilepsy

Pauline Anderson

December 17, 2018

NEW ORLEANS — Results of open-label extension trials show the recently approved drug Epidiolex (GW Pharmaceuticals), a purified formulation of cannabidiol (CBD), is safe and effective beyond a year in patients with Lennox-Gastaut Syndrome (LGS) and Dravet Syndrome, two rare and resistant epilepsy types.

"We now have long-term data to say that it still works; the efficacy is not going to drop off, and more importantly, it's still going to be safe and you're not going to learn anything new down the road," study author Anup D. Patel, MD, Section Chief of Pediatric Neurology, Nationwide Children's Hospital, and Associate Professor, Pediatrics and Neurology, Ohio State University College of Medicine in Columbus, told Medscape Medical News.

The study was presented here at the American Epilepsy Society (AES) 2018 Annual Meeting.

Mechanism Unclear

The LGS extension study included 366 patients, mean age 16 years, who were taking a mean of three antiepileptic drugs (AEDs). Of these, 52% were taking clobazam (Onfi, Lundbeck) and 38% were taking valproic acid (Depakene, AbbVie).

The median follow-up was 61 weeks. About 24% had withdrawn from the study at the time of the analysis.

The mean dose of the drug in the LGS extension trial was 23 mg/kg/day.

In this trial, about half the patients had 50% or greater reduction in seizure frequency. Seizure reduction endpoints were maintained in 36% to 40% of patients, and about 10% of patients were seizure-free after 1 year, said Patel.

"That's a really big endpoint for a very-difficult-to-treat epilepsy syndrome, so we are pretty excited about that," he said.

In this study, the CBD dose could be as high as 30 mg/kg/day. "But when we looked at the difference between 20 and 30 mg, there did not seem to be that much more efficacy with the higher dose," said Patel.

The precise mechanisms by which purified CBD exerts its anticonvulsant effect remains unknown. However, additional research released at the AES meeting suggests a unique multimodal action at three novel targets: GPR55 receptors; TRPV1 channels; and adenosine reuptake transporters.

Adverse events (AEs) occurred in 94% of patients and serious AEs were reported in 33% in the LGS study.

"We saw some of the same side effects," as in the pivotal trials, said Patel. "We didn't see anything new emerge."

As with the earlier trials, fatigue was the most common side effect, said Patel.

About 13% of patients had an increase in liver enzymes, but none met criteria for severe liver injury. In all but three cases, this resolved, said Patel.

"We don't know if those three cases will resolve too, but we will continue to follow them." Some 74% of the patients with elevated liver enzymes were taking valproic acid.

No Evidence of Tolerance

Similarly, results of an open-label extension trial of Epidiolex in patients with Dravet syndrome were similar, said Patel.

"The side effect profile was similar; the efficacy was very similar, and again, you see maintained endpoints, which is really exciting."

Unlike research using CBD combined with tetrahydrocannabinol (THC), there was no evidence of tolerance to Epidiolex in these open-label extension trials, said Patel.

He believes this is because "CBD works differently in the brain" than THC in terms of "where it binds and how it works."

The drug received US Food and Drug Administration (FDA) approval for LGS and Dravet Syndrome but is not approved anywhere else in the world.

Before Epidiolex could be made available to patients, the US Drug Enforcement Administration (DEA) had to lower its restriction classification based on its low potential for abuse. In September of this year, the drug was rescheduled from Schedule I to Schedule V, the lowest restriction classification. 

"Very Encouraging" Findings

Commenting on the findings for Medscape Medical News, Daniel M. Goldenholz, MD, PhD, Instructor in Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, noted that the overall large percent of patients who are tolerating the medication is "very encouraging."

"It's certainly very exciting that we have another treatment option for people who are very sick." However, he added, his enthusiasm is somewhat "tempered" with regard to some of the efficacy results.

For example, in the 10% of study patients who appeared to be seizure-free, Goldenholz pointed out that one of the unknowns about the natural history of epilepsy is the extent to which one can expect patients who are drug-resistant "to appear to be seizure free" for a period of time.

"This comes up in many open-label extension trials where there is no control comparison group; indeed, we see some small percentage of patients who become seizure-free in many such trials, including those with drug and device and surgery interventions," Goldenholz said.

Some patients may have seizure freedom for a time, and then go back to having seizures, added Goldenholz. "It makes me wonder, are we looking at an effect of the drug or effect of the disease? Without a control group, it's very hard to be sure."

Although the responder rate of patients in the study is also encouraging, the concern is "whether this outcome is what patients and families are looking for — a 50% response means you still have seizures," he said.

Dr Patel has consulted for, conducted studies funded by, or received honoraria from GW Pharmaceuticals. Dr Goldenholz has received grants from the NIH and from a Beth Israel Deaconess Medical Center department of neurology grant, and serves as an advisor for Magic Leap. The Epidiolex studies were supported by GW Research Ltd.

American Epilepsy Society (AES) 2018 Annual Meeting. Abstract 1.298. Presented December 1, 2018.

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