A pilot, open‐label study of the effectiveness and tolerability of low‐dose ZX 008 (fenfluramine HC l) in Lennox‐Gastaut syndrome

Summary Objective Lennox‐Gastaut syndrome ( LGS ) is a drug‐resistant, childhood onset electroclinical epilepsy syndrome with multiple seizure types and diagnostic electroencephalogram findings. ZX 008 (fenfluramine HC l oral solution) was well tolerated and reduced seizure frequency in Dravet syndrome, prompting this phase 2, open‐label, dose‐finding study of add‐on ZX 008 in patients with LGS ( NCT 02655198). Methods Eligible treatment‐refractory patients with LGS aged 3‐18 years with ≥4 documented convulsive seizures ( CS ) in the prior 4 weeks were administered adjunctive ZX 008 twice daily at an initial dose of 0.2 mg/kg/d, with incremental dose escalations up to 0.8 mg/kg/d or 30 mg/d (maximum dose) every 4 weeks in nonresponders (<50% reduction in CS frequency). After 20 weeks (core study), responders were offered entry into a long‐term extension study. Seizures were captured via diary. Cardiac safety was monitored by Doppler echocardiography and electrocardiogram. Results Thirteen patients were enrolled (mean age = 11.7 years, range = 3‐17). Ten (77%) patients completed 20 weeks of ZX 008 treatment. During the core study, there was a 53% median reduction (N = 13) in CS ; median reduction was 60% in the 10 completers. Eight patients (62%) had a ≥50% CS reduction; three (23%) patients had a ≥75% reduction. Nine (69%) patients entered the long‐term extension study. At 15 months (n = 9), median reduction in CS was 58%; six (67%) patients had a ≥50% reduction, and three (33%) patients had a ≥75% reduction. The most common adverse events were decreased appetite (n = 4, 31%) and decreased alertness (n = 2, 15%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. Significance ZX 008 provided clinically meaningful reduction (≥50%) in CS frequency in the majority of patients with LGS in this pilot study and was generally well tolerated. A phase 3, randomized, controlled study is ongoing.