IP 1184. ZX008 (Fenfluramine) in Dravet’s Syndrome: First Results of a Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial

Background: Dravet’s syndrome (DS) is a rare, severe, treatment-resistant epileptic encephalopathy. Fenfluramine (FFA) has been reported to have sustained anticonvulsive activity in a small cohort of patients with DS.

Aims: Assessment of effectiveness and safety of a new treatment option for patients with DS.

Question: FAiRE DS is a Phase 3 clinical trial comparing two doses of ZX008 and placebo on the change in mean convulsive seizure frequency in DS subjects including assessment of the safety of both doses.

Methods: Subjects aged 2 to 18 years with a diagnosis of DS and in whom convulsive seizures were not completely controlled by their current antiepileptic drug regimen were enrolled in the study. Subjects who had ≥6 convulsive seizures during the 6-week baseline period were randomized in a 1:1:1 ratio to placebo, ZX008 0.2, or 0.8 mg/kg/d (maximum 30 mg/d). 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 end point was the change in mean convulsive seizure frequency (cerebrospinal fluid [CSF]) between ZX008 0.8 mg/kg/d and placebo during the 14-week treatment period compared with the 6-week baseline observation period.

Results: A total of 119 subjects with DS enrolled in the study and were randomized to treatment (n = 39, 0.2 mg/kg/d; n = 40, 0.8 mg/kg/d; n = 40, placebo). The average age of the subjects was 8 years (range: 2–18 years). One hundred ten (92%) patients completed the study (100% 0.2 mg/kg/d; 85% 0.8 mg/kg/d; 93% placebo). The baseline means CSF across treatment groups was ∼40 seizures/month. For the primary end point, ZX008 0.8 mg/kg/d achieved 63.9% reduction in mean monthly CSF compared with placebo (p < 0.001). The median percent reduction in monthly CSF was 72.4% among ZX008 0.8 mg/kg/d patients compared with 17.4% in placebo patients (p < 0.001).

A significantly greater proportion of subjects in ZX008 groups achieved ≥50% or ≥75% reduction in mean CSF and longer median seizure-free interval compared with placebo, with 0.8 mg/kg/d superior to 0.2 mg/kg/d on all end points. Collectively, these data suggest a dose response relationship. In a subanalysis of the data, ZX008 also demonstrated robust antiseizure activity in subjects who had previously failed treatment with stiripentol, which is currently the only treatment approved for DS.

The incidence of serious adverse events was similar in all three groups with 12.5% (n = 5) of patients in the 0.8 mg/kg/d group and 10.3% (n = 4) of patients in the 0.2 mg/kg/d group experiencing at least one treatment emergent serious adverse event compared with 10.0% (n = 4) of patients in the placebo group. Prospective cardiac safety monitoring throughout the study demonstrated no clinical or echocardiographic evidence of cardiac valvulopathy or pulmonary hypertension.

Conclusion: Patients treated with ZX008 experienced statistically significant, clinically meaningful reductions in mean CSF compared with patients treated with placebo, with the 0.8 mg/kg/d dose superior to 0.2 mg/kg/d. 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.

This study was financed by Zogenix, Inc.