Abstracts

Rationale: Dravet syndrome (DS) is a rare, severe, treatment-resistant epileptic developmental encephalopathy. Fenfluramine (FFA) has been reported to have sustained anti-convulsive activity in a small cohort of patients with DS. Here we describe the results of a Phase 3 clinical trial comparing two doses of ZX008 vs placebo for the change in convulsive seizure frequency (CSF) in DS patients. Methods: Patients 2-18 years old with a diagnosis of DS and in whom convulsive seizures were not completely controlled by their current anti-epileptic drug regimen were enrolled. Patients who had =6 convulsive seizures during the 6-week baseline period were randomized in a 1:1:1 ratio to ZX008 0.8 mg/kg/day (maximum 30 mg/day), 0.2 mg/kg/day, or placebo. Daily doses were administered BID. After a 2-week titration period patients were maintained on their randomized dose for an additional 12 weeks. The number and type of seizures were recorded daily in an electronic diary by caregivers. The primary efficacy endpoint was the change in mean monthly CSF between ZX008 0.8 mg/kg/day and placebo during the 14-week treatment period compared to the 6-week baseline observation period. Results: A total of 119 patients with DS enrolled in the study and were randomized to treatment (n=40, 0.8 mg/kg/day; n=39, 0.2 mg/kg/day; n=40, placebo). The mean age of the patients was 9 years (range: 2-18 years). 110 patients (92%) completed the study (85% 0.8 mg/kg/day; 100% 0.2 mg/kg/day; 93% placebo). Baseline mean CSF across treatment groups was ~40 seizures/month. For the primary endpoint, ZX008 0.8 mg/kg/day showed a 63.9% reduction in mean monthly CSF vs placebo (p<0.001). The median percent reduction from baseline in monthly CSF was 72.4% for ZX008 0.8 mg/kg/day patients vs 17.4% for placebo patients (p<0.001). A significantly greater proportion of patients in the ZX008 groups achieved a =50% or =75% reduction in CSF and a longer median seizure-free interval vs placebo (Table 1), with 0.8 mg/kg/day exceeding 0.2 mg/kg/day on all endpoints, suggesting a dose-response relationship. The incidence of treatment-emergent serious adverse events was similar in all 3 groups (Table 2). Prospective cardiac safety monitoring throughout the study demonstrated no clinical or echocardiographic evidence of cardiac valvulopathy or pulmonary hypertension. Conclusions: Patients treated with ZX008 experienced statistically significant, clinically meaningful reductions in CSF compared with patients treated with placebo. ZX008 was generally well tolerated, with no clinical and/or echocardiographic signs of valvulopathy or pulmonary hypertension. ZX008 may represent an important and effective new treatment option for patients with DS. Funding: This study was funded by Zogenix, Inc.