Abstracts

Rationale: Lennox Gastaut Syndrome (LGS) remains a very drug-resistant childhood-onset epilepsy with different etiologies and characterized by multiple seizures types and diagnostic EEG findings. Fenfluramine has been shown to have a beneficial effect on different seizure types in children with Dravet syndrome. We hypothesized that add-on low dose fenfluramine (ZX008) might also significantly reduce seizure frequency in LGS. Methods: LGS patients 3-18 years of age who had failed multiple therapies are eligible to enroll in this ongoing Phase 2 pilot open-label, dose finding trial of ZX008 as an add-on therapy. Subjects must be diagnosed with LGS as described by the ILAE diagnostic criteria; with at least 4 documented convulsive seizures and on at least 2 AEDs at stable doses in the last 4 weeks for eligibility. After the initial 4-week baseline period to record seizure frequency, ZX008 is initiated at a dose of 0.2 mg/kg/day. Subjects who do not achieve at least 50% reduction in seizure frequency have their dose increased every 4 weeks, in increments of 0.2 mg/kg/day up to a maximum dose of 0.8 mg/kg/day (or max 30 mg/day) for up to 20 weeks. Results: Interim results are described for the first 10 patients (8 male, 2 female) who have been on ZX008 treatment for at least 8 weeks. In 4 patients, an etiology could be identified (3 genetic causes, one structural). Mean age at the start of ZX008 treatment was 12.1 years (range 3 to 17 years). At the start of ZX008 treatment patients were taking an average of 3.1 AEDs (range 2-4), which included valproate in all patients and at least one other AED or treatment, most frequently benzodiazepines (6/10), vagus nerve stimulation (6/10), lamotrigine (4/10) and/or rufinamide (4/10). The median number of convulsive seizures during the 4-week baseline was 44 (range 21-1360). Six of the 10 patients (60%) achieved at least a 50% reduction in the number of convulsive seizures during the first 8 weeks of the study at doses of 0.2mg/kg (2 patients) and 0.4mg/kg (4 patients). The median monthly convulsive seizure frequency reduction compared to baseline for all 10 patients (ITT population) was 50.5% with 3 patients experiencing a >75% reduction in convulsive seizure frequency. Drug related AEs were experienced by 5 patients and included decreased appetite (2/10), sleep problems (2/10), sleepiness (1/10) and decreased alertness (1/10). Two patients withdrew due to AEs (decreased alertness (n=1), sleep problems (n=1) and lack of efficacy. No clinical signs or symptoms of cardiovascular AE’s have been observed. Conclusions: In this first pilot study, interim results after at least 8 weeks of treatment show that ZX008 provides clinically meaningful improvement in convulsive seizure frequency in patients with refractory LGS, while being generally well tolerated.  A dose response appears to be emerging with more patients become responders at the 0.4mg/kg/day vs. 0.2mg/kg/day (Figure).  It is important to note that ZX008 doses were not titrated to maximal benefit for these LGS patients as per protocol. Funding: This investigator initiated trial was supported by Zogenix.