Two potential drugs to treat Dravet syndrome


Phase III clinical trials of new antiepileptic medications show promise for reducing frequency of convulsive seizures in children.

Recent results of a phase III trial showing the efficacy of a new drug to treat Dravet syndrome is adding to the expectation that a better way to treat this difficult type of epilepsy in children will soon be available.

In late September, the first published results of a phase III trial of the drug ZX008 (Zogenix Inc.; Emeryville, California) showed its efficacy in significantly reducing the frequency of seizures in patients with Dravet syndrome.1 These results come on the heels of results published first in 2016 and later in 2017 of the efficacy of another drug, the cannabidiol-based agent Epidiolex (GW Pharmaceuticals; Cambridge, United Kingdom), for this syndrome.2

“Both drugs show promise,” says Jacqueline French, MD, professor of Neurology and director of Translational Research and Clinical Trials Epilepsy, New York University Comprehensive Epilepsy Center, New York, New York.

The need to find an effective treatment for Dravet syndrome is underscored by the lack of efficacy of standard antiepileptic treatments to control the frequent and prolonged seizures experienced by children with this syndrome. Also known as severe myoclonic epilepsy of infancy (SMEI), Dravet syndrome is a rare condition that typically begins in an infant’s first year of life and can result in cognitive and developmental impairment as well as uncontrolled seizures.

Newest data: ZX008

The most recent data comes from the first of 2 trials evaluating the efficacy of ZX008 (low-dose fenfluramine hydrochloride) to treat Dravet syndrome. In the phase III controlled trial, 119 children with Dravet syndrome were randomized to ZX008 0.8 mg/kg/day (30 mg maximum daily dose; n=40), ZX008 0.2 mg/kg/day (n=39), and placebo (n=40) in addition to the current antiepileptic drugs they were taking and following a 6-week baseline observation period. After a 2-week period of dose titration to their target dose, all patients remained on the fixed dose for 12 weeks.1

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The primary outcome of the study was the change in mean monthly convulsive seizure frequency between ZX008 at the higher dose (0.8 mg/kg/day) and placebo over the 14 weeks of treatment compared with the 6-week baseline observation period. A similar analysis that compared ZX008 at the lower dose (0.2 mg/kg/day) and placebo was done as a secondary outcome.

Based on the primary outcome of the study, investigators found a significant reduction in mean monthly convulsive seizures in patients taking ZX008 (0.8 mg/kg/day) compared with placebo (72.4% vs 17.4%; P<.001), representing an overall 63.9% reduction. Patients treated at the lower dose of ZX008 also had a significant reduction in mean monthly convulsive seizures by 33.7% compared with placebo (P=.019).

In addition, the study found that the proportion of patients with ≥50% reduction in monthly convulsive seizures was significantly greater in patients treated with ZX008 0.8 mg/kg/day and ZX008 0.2 mg/kg/day compared with placebo (70% and 41%, respectively, vs 7.5% placebo; P<.001 for both comparisons). Similar outcomes were seen for the proportion of patients with ≥75% reduction in monthly convulsive seizures (45% and 20.5%, respectively, vs 2.5% placebo; P<.001 and P=.033, respectively).

Patients treated with ZX008 at both dose levels (0.8 mg/kg/day and 0.2 mg/kg/day) had more treatment-related adverse events compared with placebo (95% and 94.9% vs 65%, respectively), but adverse events were similar among the 3 groups.

“The results of the Zogenix [manufacturer of ZX008] trial are really striking,” says French, “and suggest a substantial benefit in this difficult syndrome.”

However, she cautions about the potential risks associated with chronic use of fenfluoramine including the risk of valvular problems and pulmonary hypertension. “To date, this has not been seen definitively in children with Dravet treated with low-dose fenfluoramine, but it is too early to exclude the possibility with longer-term use.”


The latest results of the efficacy of Epidiolex were published in May 2017 showing the efficacy of this cannabidiol-based drug to reduce the frequency of convulsive seizures compared with placebo. The trial included 120 children and young adults with Dravet syndrome randomized to Epidiolex (20 mg/kg/day) or placebo in addition to standard treatment.2

The primary outcome of the study was change in the frequency of convulsive seizures over the 14 weeks of treatment compared with a 4-week baseline period.

The study found a significant reduction in the median frequency of convulsive seizures per month in patients treated with Epidiolex (12.4 to 5.9) compared with those in the placebo group (14.9 to 14.1), representing a 22.8 percentage point decrease between the 2 groups (P=.01). In addition, the study found that more patients treated with Epidiolex had a 50% reduction in the frequency of their convulsive seizures compared with patients in the placebo group (43% vs 27%; P=.08).

The study also found that patients treated with Epidiolex had more frequently occurring adverse events, including vomiting, diarrhea, pyrexia, fatigue, somnolence, and abnormal test results on liver function.

“Epidiolex also shows benefit,” says French. However, she highlighted that over half the children in the study were on the background medication clobazam and that Epidiolex is known to interact with clobazam by increasing its metabolism to norclobazam.

“This is problematic because it leaves open the possibility that some of the improvement in seizures seen in the studies were due to increased exposure to norclobazam rather than directly to Epidiolex,” she said.

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Saying, however, that it is very likely that Epidiolex has independent action, French nonetheless emphasizes that “we do not have controlled data on children with Dravet who are not on clobazam.”


1. Zogenix Inc. Zogenix announces positive top-line results from pivotal phase 3 clinical trial of ZX008 in Dravet syndrome [news release]. Available at: Published September 29, 2017. Accessed October 13, 2017.

2. Devinsky O, Cross JH, Laux L, et al; Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Eng J Med. 2017;376(21):2011-2020.

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