Abstracts

Rationale: We have previously reported the beneficial therapeutic effect of fenfluramine (ZX008) in patients with Lennox-Gastaut Syndrome (LGS), a drug-resistant childhood-onset epilepsy with different etiologies and characterized by multiple seizure types and diagnostic EEG findings. We now report updated results from these 13 patients who have completed the study. Enrollment is ongoing. Methods: This is an ongoing Phase 2 pilot open-label, dose-finding trial of ZX008 as add-on therapy for LGS in patients 3-18 years of age who had failed multiple therapies. Subjects were diagnosed with LGS as described by the ILAE diagnostic criteria with at least 4 documented major motor seizures and were receiving at least 2 AEDs at stable doses in the 4 weeks previous to enrolment for eligibility. After the initial 4-week baseline period to record seizure frequency, ZX008 was initiated at a dose of 0.2 mg/kg/day. Subjects who did not achieve at least 50% reduction in seizure frequency had their dose increased every 4 weeks up to a maximum dose of 0.8 mg/kg/day (or max 30 mg/day) for up to 20 weeks. Results: Thirteen patients (9 male, 4 female) have completed the study; (10 [77%] completed 20 weeks of treatment, 3 discontinued). In 6 patients, an etiology could be identified (4 genetic causes, 2 structural). Mean age at the start of ZX008 treatment was 11.7 years (range 3-17 years). At the start of ZX008 treatment patients were taking a median of 4 antiepileptic treatments (range 2-4), which included valproate (11/13), a benzodiazepine (8/13), vagus nerve stimulation (7/13), lamotrigine (5/13), and/or rufinamide (4/13). Prior to the study, a median of 5 AEDs (range 3-7) had failed over a period of 7.5 years due to insufficient efficacy or intolerable side effects. The median number of major motor seizures during the 4-week baseline was 60 (n=13; range 21-1360). End of Study median seizure frequency was 31 (n= 13, range 2-890; p 75% reduction in convulsive seizure frequency (see Table). Drug-related AEs were experienced by 7 patients and included decreased appetite (3/13), sleep problems (2/13), decreased alertness (2/13), sleepiness (1/13), and fatigue (1/13). Three patients withdrew due to lack of efficacy and/or AEs [decreased alertness (n=2), insomnia (n=1)]. No clinical signs or symptoms of cardiovascular AE’s have been observed, including on echocardiography. Conclusions: The interim results of this study suggest that ZX008 provides clinically meaningful improvement in convulsive seizure frequency in refractory LGS patients, while being generally well tolerated. Given the study was designed for signal detection, it is important to note that ZX008 doses were only titrated until a =50% response was achieved; they were not titrated to maximal benefit as per protocol. A phase 3 randomized controlled study is ongoing to validate these findings. Funding: This trial was supported by a research grant from Zogenix.