Safety and Effectiveness of Fenfluramine for the Treatment of Seizures in Lennox-Gastaut Syndrome: Results From the Final Analysis of an Open-Label Extension Study
Kelly Knupp1, Ingrid Scheffer2, Berten Ceulemans3, Joseph Sullivan4, Katherine Nickels5, Lieven Lagae6, Renzo Guerrini7, Sameer Zuberi8, Rima Nabbout9, Kate Riney10, Michael Lock11, David Dai12, Ronald Davis13, Diego Morita14, Amélie Lothe14, Mélanie Langlois14, Rebecca Zhang-Roper14, Timothy Minh14, Antonio Gil-Nagel15
1Children's Hospital Colorado, 2University of Melbourne, Austin Hospital and Royal Children's Hospital, Florey and Murdoch Children’s Research Institutes, 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, 7Meyer Children’s Hospital IRCCS, and University of Florence, 8Paediatric Neurosciences Research Group, Royal Hospital for Children, 9Member of European Reference Network EpiCARE, Reference Centre for Rare Epilepsies, Necker Enfants Malades Hospital, APHP, U 1163 Institut Imagine, Université Paris Cité, 10The University of Queensland, St Lucia; Queensland Children's Hospital, 11Independent Statistical Consultant, 12Syneos Health, 13Neurology and Epilepsy Research Center, 14UCB, 15Hospital Ruber Internacional
Objective:
To describe the final long-term safety and effectiveness data from a fenfluramine (FFA) open-label extension (OLE) study in participants with Lennox-Gastaut syndrome (LGS) (NCT03355209).
Background:
LGS is a developmental and epileptic encephalopathy characterized by tonic seizures and other seizure types, intellectual impairment and specific electroencephalogram findings. In a randomized controlled trial (RCT, Cohort A), FFA 0.7 mg/kg/day demonstrated a 26.5% median reduction in seizures associated with a drop vs 7.6% in the placebo group (P=0.001). In an interim analysis of this OLE study, FFA demonstrated a median reduction in frequency of seizures associated with a drop of 28.6% (P<0.0001) over the OLE (n=241).
Design/Methods:
Participants started on FFA 0.2 mg/kg/day, then flexibly titrated to effectiveness/tolerability after 1 month. Wilcoxon signed-rank test was used for median percent change from RCT baseline (from Month 1–end of study) in seizures associated with a drop. Additional methods have been described [Knupp 2023 Epilepsia].
Results:
247 participants (mean age 14.3±7.6 years) were enrolled in the OLE; disposition unknown in 3/247 participants, 158/244 completed the study, and 86/244 discontinued FFA (13/86 due to adverse event). Median treatment duration was 364 days (range, 19-537). 205 (83.0%) participants experienced ≥1 treatment-emergent adverse event (TEAE). Of 41 participants with ≥1 serious TEAE, 12 had ≥1 related to FFA. TEAEs reported in ≥10% of participants were: decreased appetite (16.2%), fatigue (13.4%), nasopharyngitis (12.6%), seizure (10.9%), pyrexia (10.1%). No cases of valvular heart disease or pulmonary arterial hypertension were observed. Median decrease in frequency of seizures resulting in drop over the OLE (n=241) was 29.5% (P<0.0001).
Conclusions:
In this final analysis of an OLE study in participants with LGS, FFA was generally well tolerated with no new safety signals. FFA was associated with a sustained reduction in seizures, confirming FFA as an important treatment option for patients with LGS.
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