Cannabidiol Reduces Seizures in Various Epilepsy Disorders

Pauline Anderson

December 05, 2016

HOUSTON — A purified oral formulation of cannabidiol (CBD; Epidiolex, GW Pharmaceuticals) significantly reduces seizures in treatment-resistant epilepsy, according to new research that included double-blind randomized controlled trials of patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), two of the most difficult-to-manage seizure conditions.

The new research, released here at the American Epilepsy Society (AES) 2016 Annual Meeting, also highlights the relative safety of this new drug, a prescription medicine derived from the cannabis plant.

Elizabeth A. Thiele, MD, PhD, director, Pediatric Epilepsy Program, Massachusetts General Hospital, and professor, neurology, Harvard Medial School, Boston, who contributed to many of the studies, told Medscape Medical News she is excited about the results.

"It's exciting because at least for a portion of people with Dravet and with Lennox-Gastaut, it's going to be an effective treatment, and what I can see with my experience with the expanded-access program, it's going to be an effective treatment for other people as well."

Dr Thiele estimates that more than 1000 patients now have access to the drug through this expanded program.

Only once before in her career has she seen an effective epilepsy treatment come into being because of a push from the epilepsy community. The other was the very-low-carbohydrate ketogenic diet, which was at first shunned by the medical community but is now being used or tested not only in epilepsy but also in other neurologic disorders and in cancer.

It has been "quite a journey" for this new CBD product, said Dr Thiele. Only a few years ago, many epilepsy experts doubted that the drug works and thought that any effects were due to a placebo effect. It took hard work and social media exposure to get the ball rolling in terms of formal testing of this medical cannabis product.

Much of the new research includes patients with LGS, an epilepsy syndrome due to many different causes, and DS, which is mostly a single-gene disorder. Both are rare seizure conditions that typically start in childhood.

Researchers initially carried out a safety study in children with DS who were randomly assigned to one of three doses of CBD (5, 10, or 20 mg/kg per day) or to placebo as add-on therapy for 3 weeks.

Safety data in 34 patients aged 4 to 10 years showed that the most common adverse events (AEs) were somnolence (19% in those taking CBD vs 14% in those receiving placebo), pyrexia (22% vs 0%), decreased appetite (19% vs 0%), and sedation (15% vs 0%).

Serious adverse events were reported in 5 patients (a treatment-related case of status epilepticus in the 5-mg group, a treatment-related case of pyrexia and maculopapular rash and a case of pyrexia and convulsion in the 10-mg group, and a case of parvovirus and a case of viral infection in the 20-mg group).

There were no clinically relevant changes in vital signs or electrocardiograms and no reports of suicidal behavior or ideation.

DS, LGS Studies

The larger randomized controlled trial of CBD in DS included 120 patients. The mean age was 10 years, and 29% of patient were under age 6 years. Patients in this study had tried a median of four antiepileptic drugs and at the time of the study were taking a median of three. They were randomly assigned to receive CBD 20 mg/kg per day or placebo.

The study showed that the median reduction in seizure frequency — the primary efficacy endpoint — after 14 weeks of treatment was 39% for those receiving CBD compared with 13% for those receiving placebo (P = .0123). The difference between CBD and placebo was established by the end of 4 weeks.

As with any antiepileptic drug, not all patients responded. "Even if a child has an SCN1A mutation causing them to have Dravet, they're still genetically different than another kid with Dravet," noted Dr Thiele.

Adverse events in this study occurred in 93.4% of patients receiving CBD and 74.6% of those receiving placebo. Most events in CBD recipient were mild or moderate. The most common adverse events in patients taking the active drug were somnolence, diarrhea, decreased appetite, fatigue, pyrexia, vomiting, lethargy, upper respiratory tract infection, and convulsion.

Serious adverse events were reported in 16.4% of patients taking CBD (8.2% of these were considered treatment related) and 5.1% of placebo recipient.

A second double-blind randomized controlled trial tested CBD added to concomitant antiepileptic drugs (AEDs) in children and adults with treatment-resistant LGS. Eligible patients had a history of a slow (<3 Hz) spike-and-wave pattern on electroencephalography and had experienced at least two drop seizures each week at baseline.

Researchers randomly assigned 86 patients to receive oral CBD at a dose of 20 mg/kg per day and 85 to receive a matched placebo. The mean age of these 171 patients was 15 years, with 34% of patients being 18 years or older. Study patients had been treated with a mean of six AEDs before the trial and took a mean of three during the trial.

The primary efficacy outcome was percentage change in drop seizure frequency (tonic, atonic, and tonic-clonic). The median drop seizure frequency per 28 days at baseline was 74.

At 14 weeks, seizure frequency decreased 44% in the treatment group compared with 22% in the placebo group (P = .0135). The difference between CBD and placebo emerged during the first 4 weeks of stable dosing and was sustained throughout the treatment period.

Here again, the drug was generally well tolerated. About 86% of CBD and 69% of placebo recipients had adverse events, and most in the treatment group were mild or moderate.

The most common events in patients taking CBD were diarrhea, somnolence, pyrexia, decreased appetite, and vomiting. Serious adverse events were reported in 20 CBD recipients (9 of which were considered treatment-related) and in 4 placebo recipients.

Although patients in both trials experienced appetite loss, Dr Thiele pointed out that they didn't lose weight (perhaps because they were taking the medicine in oil). "Decreased appetite and weight loss are different things; if they had weight loss, that would have been concerning in a pediatric population," she said.

Dr Thiele also noted that the safety profile of CBD is better than that of some AEDs, which can cause cognitive side effects and require regular blood monitoring.

Another randomized trial in LGS compared CBD at 10 mg and 20 mg/kg per day, but the analysis was not complete in time to be presented at the AES meeting. A study will test the drug in patients with tubular sclerosis complex, Dr Thiele said.

Elsewhere, an open-label study of Epidiolex was carried out in 81 pediatric and adult patients in Alabama who had treatment-refractory epilepsy. They started at a dose of 5 mg/kg per day with adjustments up to a maximum of 50 mg/kg per day.

This study found significant seizure reduction for all patients at 3 months (P = .007) and 6 months (P = .002), with the most optimal dose of CBD being 20 mg/kg/day at 3 months and 25 mg/kg per day at 6 months.

"What all these studies definitely show is that CBD, in this form, is clearly an effective treatment option, although it might not be the final word on what marijuana compounds can do in epilepsy," said Dr Thiele. She stressed that the study participants "are some of the most highly refractory patients we have."

Best Control

She related several individual CBD success stories. One is a young man with LGS who experienced "the best seizure control that he's every had" after starting CBD and is now seizure-free (after adding a "tiny dose" of clobazam, according to Dr Thiele).

A young girl in whom no drug had succeeded in controlling her seizures had just acquired a guide dog when she began CBD. She has now been seizure free for 2.5 years. A picture posted on the Internet depicts her dog on a beach in flip flops holding a sign saying he's happily retired.

So far, the efficacy of the drug hasn't been lost in any of Dr Thiele's patients. "But I think we see a honeymoon period for all of our treatments…. Some people will probably lose efficacy with time."

Drug interactions with other AEDs are a concern, however. Researchers have noted significant interactions with clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine.

From her experience with about 80 pediatric patients between the trials and the open-label access, Dr Thiele said the drug is "extremely well tolerated," but many of the side effects that do come up are due to medication interactions.

A particular concern is with clobazam, she said. "So many kids are on medical marijuana and may also be taking clobazam."

Both drugs are metabolized through the liver, and while levels of clobazam may not change with addition of CBD, its active metabolite, desmethylclobazam, "can skyrocket."

But should the drug be approved, GW Pharmaceutical will make sure clinicians are aware of such interactions, said Dr Thiele.

A "bigger issue," she said, is that some patients with epilepsy aren't telling their clinician that they're using medical marijuana. "I think physicians should be more proactive about asking their patients if their patients are using it."

She herself encourages her patients to be open with her, but she recognizes that some doctors don't want to know that their patients are using medical marijuana. They may be concerned about their liability and would have to report the patient to authorities.

GW Pharmaceuticals (which in the United States now operates as Greenwich Biosciences Inc) is preparing to request fast-track status for Epidiolex to treat DS and LGS from the US Food and Drug Administration early next year, said Dr Thiele.

Promising Approach

The CBD research was discussed elsewhere at the meeting. During a presentation on current and future trends in developing AEDs at the Presidential Symposium, Henrik Klitgaard, PhD, vice president, Neuroscience Therapeutic Area, UCB, Belgium, called the use of CBD to control seizures "a very promising approach."

In his address, Dr. Klitgaard cited a recent review suggesting that 65 potential mechanisms may be involved in the effect of CBD.

"It seems most likely that the antiepileptic effect of cannabidiol may derive from ion channel targets in particular."

Ion channels are among the targets of a many CBD pharmaceutical candidates. Other targets include enzyme, transporter, and receptor targets.

For a comment on this new research, Medscape Medical News approached Michael R. Sperling, MD, Baldwin Keyes Professor of Neurology, Director, Jefferson Comprehensive Epilepsy Center, Sidney Kimmel Medical College, Philadelphia.

Dr Sperling questioned how much of the effect for patients on clozapam who add CBD "is really from CBD vs just making the other drug higher."

He agreed with Dr Thiele that doctors should be aware that patients are taking medical marijuana.

"When you put people on any drug, you really need to go deeply into what other substances they're taking, not only drugs and medical marijuana, but other recreational drugs and for that matter supplements and herbs," he said. "Large numbers of the American population use these and we need to know what they're taking because they all have the potential for interactions."

The studies were funded variously by GW Research Ltd and the State of Alabama.

American Epilepsy Society (AES) 2016 Annual Meeting. Abstracts 1.377, 1.186, 2.100, 2.208, 2.361, and 2.362. Presented December 3 and 4, 2016.

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