Interim Analysis of Long-Term Safety and Efficacy of FINTEPLA (fenfluramine) in Patients with Lennox-Gastaut Syndrome
Kelly Knupp1, Ingrid Scheffer2, Berten Ceulemans3, Joseph Sullivan4, Katherine Nickels5, Lieven Lagae6, Renzo Guerrini7,8, Sameer M Zuberi9, Rima Nabbout10, Kate Riney11,12, Svetlana Shore13, Anupam Agarwal13, Michael Lock13, Gail Farfel13, Bradley Galer13, Arnold Gammaitoni13, Ronald Davis14, Antonio Gil-Nagel15
1Children's Hospital Colorado, 2University of Melbourne, Austin Hospital and Royal Children’s Hospital, 3Antwerp University Hospital, 4University of California San Francisco Weill Institute for Neurosciences, Benioff Children’s Hospital, 5Mayo Clinic, 6Member of the European Reference Network EpiCARE; University of Leuven, 7Anna Meyer Children’s Hospital, University of Florence, 8IRCCS Fondazione Stella Maris, 9Paediatric Neurosciences Research Group, Royal Hospital for Children, 10Reference Centre for Rare Epilepsies, Necker-Enfants Malades Hospital, Université de Paris, Imagine Institute, 11Queensland Children’s Hospital, 12School of Clinical Medicine, University of Queensland, 13Zogenix, Inc., 14Neurology and Epilepsy Research Center, 15Hospital Ruber Internacional
To evaluate the long-term safety and efficacy of fenfluramine in patients with Lennox-Gastaut syndrome (LGS).
LGS is a treatment-resistant developmental and epileptic encephalopathy (DEE) with multiple seizure types and high rates of morbidity and mortality. During the randomized controlled trial, patients with LGS treated with fenfluramine 0.7 mg/kg/day demonstrated a 26.5% median reduction in seizures associated with a drop vs 7.6% in the placebo group, with an estimated median difference of -19.9% (P=0.0013).
Eligible patients with LGS who completed a 14-week phase 3 randomized clinical trial enrolled in an open-label extension (OLE; NCT03355209). All patients were initially started on 0.2 mg/kg/day fenfluramine and were titrated to effectiveness/tolerability after 1 month. Effectiveness/tolerability were assessed at 3-month intervals.
247 patients were enrolled in the OLE as of the data cut-off for this interim analysis (10/19/2020). Mean age was 14.3±7.6 years (79 [32%] adults, 18 years). The 5 most common concomitant antiseizure medications (ASM) were valproate, clobazam, lamotrigine, levetiracetam, and rufinamide; 88.3% of patients received 2-4 concomitant ASMs. Median percentage decrease in monthly frequency of seizures resulting in drops (hereafter “drop seizure frequency”) at Month 3 was ‑39.4% and was sustained up to 12 months (-51.8%) By the end of Months 10-12 in the OLE period, 87 patients (51.2%) experienced ≥50% reduction in drop seizure frequency, and approximately 50% of investigators and caregivers rated patients as “Much Improved”/“Very Much Improved”. The 2 most frequent treatment-emergent adverse events during the entire OLE period were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. 
Patients with LGS experienced sustained (39.4%-51.8% ) reduction in drop seizure frequency during fenfluramine treatment from 3-12 months. Fenfluramine was generally well tolerated; VHD or PAH was not observed long-term. Fenfluramine may provide an important new treatment option for LGS.