Does CBD's Approval Mark a Turning Point for Treatments in Dravet Syndrome?

Dennis J. Dlugos, MD, MSCE, the director of the Epilepsy Program at Childrens Hospital of Philadelphia

Dennis J. Dlugos, MD, MSCE

In 2018, the armamentarium of epilepsy therapies in the United States has grown by 2, with the FDA granting approval to cannabidiol (CBD; Epidiolex, GW Pharmaceuticals) and stiripentol (Diacomit, Biocodex) for a pair of epilepsy syndromes: Dravet and Lennox-Gastaut (LGS).

In a Hot Topics presentation at the American Epilepsy Society’s 72^nd annual meeting in New Orleans, Louisiana, Dennis J. Dlugos, MD, MSCE, the director of the Epilepsy Program at Children’s Hospital of Philadelphia, highlighted these 2 approvals and discussed the impact that these approvals, specifically CBD, has had on clinical care and practice.¹

While stiripentol’s approval came in with more of a “whisper,” as Dlugos put it, mainly because it has been approved for use in the European Union for more than a decade, CBD’s approval came in with a “bang.” And although Dlugos began his talk by noting that the field needs to focus on objective data and not hype alone, he also acknowledged that the data for CBD’s approval has been satisfactory.

“There’s been some hype about CBD, but now there’s also real data with a control group in 2 different epilepsy syndromes,” he said. “That’s hot news.”

For Dlugos, the biggest takeaway has been the impact on Dravet syndrome. He said that the use of rigorous, controlled studies has led to the approval of these therapies, specifically CBD, in a condition that has long-struggled to field a solid treatment, as patients are often resistant to therapies.

“When the initial studies of Dravet syndrome were planned, it was not a sure bet that this was going to be a very study-able syndrome,” Dlugos explained. “Dravet has some factors that are not necessarily favorable if you want to do a study. Patients can have infrequent, prolonged seizures; they can have variable seizure flurries, difficult-to-count seizures—how long does the baseline phase need to be given that? Four weeks, 6 weeks, 8 weeks? Is a clinical diagnosis enough? Is a genetic diagnosis enough? So, it was by no means, 5 years ago, a sure bet that we would be able to do a standard clinical trial and show efficacy in Dravet syndrome.”

As Dlugos would then point out, those concerns have been overcome by well-done studies. For CBD, the data has been promising. In a clinical trial of the therapy in Dravet syndrome conducted by Devinsky, et al., which supported its regulatory approval, the treatment showed a 39% reduction in convulsive seizures, compared to a 13% reduction seen with placebo (P = .01).² As Dlugos pointed out, the findings for CDB for the treatment of LGS were essentially identical in efficacy and adverse effects.

One of the important points Dlugos stressed was that while the data is there, and the therapy was overall well-tolerated, there are some adverse effects with the treatment—as with almost all treatments in epilepsy.

“There were [adverse] effects—there are always [adverse] effects—and CBD has [adverse] effects,” Dlugos said. “For example, in the CBD trial, and I’m going to quote percentages here: 31% diarrhea, 28% decreased appetite, and 36% somnolence. [While there are] ways, perhaps, to minimize those, but there are [adverse] effects to CBD. They’re reversible if you stop it, and they’re not life-threatening, but there are [adverse] effects.”

Dlugos also stressed the need to understand the drug-to-drug interactions with CBD, as often patients with epilepsy syndromes are on multiple medications to address multiple seizure types. He detailed that, as is oft discussed, CBD inhibits CYP2C19, which may increase the clobazam metabolization by 3-fold.

“CBD is metabolized by CYP2C19 and CYP3A4, which means co-therapy with clobazam may increase CBD levels and co-therapy with our traditional enzyme inducers [phenobarbital, phenytoin, and carbamazepine] may decrease CBD levels,” Dlugos explained. This hasn’t gotten enough, or as much, press as the fact that CBD inhibits CYP2C19.”

Additionally, in an expanded access program study of the therapy by Szaflarski, et al., which notably did not have a control group, 52% of more than 600 patients with treatment-resistant epilepsy reported a ≥50% reduction in seizures, and 11% reported being seizure-free over a period ranging from 12 to 96 weeks.³

In this study, CBD was given in an initial dose of 2 mg/kg to 10 mg/kg daily, with the ability to titrate up to 25 mg/kg to 50 mg/kg per day. Notably, this data allowed for a very important takeaway: a better understanding of the best-tolerated dose.

“The approvals were obtained, and that’s big news. But how do we use the drug?” Dlugos said. “It was best tolerated at less than 10 mg/kg per day. One of the objectives of this symposium is to give the audience pearls or tips. How do you get pearls and tips for drugs that just hit the market? Well, this is one of them. CBD is best tolerated at less than 10 mg/kg per day.”

According to the FDA’s label for CBD, which Dlugos noted is extremely straightforward. After making baseline assessments, the agency recommends beginning at 5 mg/kg per day for a week, and then increase up to 10 mg/kg per day if needed, followed by an additional if-needed increase to 15-20 mg/kg per day.

“Some might say that if you can, perhaps begin at 2.5 mg/kg per day. Perhaps that would improve tolerability,” Dlugos noted. “The label is sort of hinting to start low, go slow, as with many things. Maybe, even start lower and go slower than the label recommends.”

REFERENCES

1. Dlugos DJ. Hot Topics: What’s in the AED pipeline? Presented at: American Epilepsy Society annual meeting; New Orleans Louisiana; December 1, 2018.

2. Devinsky O, Cross JH, Laux L, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017; 376:2011-2020.

3. Szaflarski JP, Bebin EM, Comi AM. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results. Epilepsia. 2018;59(8):1540-1548. doi: 10.1111/epi.14477