Impact of Fenfluramine on Drop Seizure Frequency in Adults or Dose-Capped Patients With Lennox-Gastaut Syndrome: Comparative Analysis of Clinical Trial Data
Kelly G. Knupp, MD, MSCS, FAES1, Ingrid E. Scheffer, MBBS, PhD, FRACP, FRS2, Berten Ceulemans, MD, PhD3, Joseph Sullivan, MD4, Katherine C. Nickels, MD, FAES, FAAN5, Lieven Lagae, MD6, Renzo Guerrini, MD, FRCP7, Sameer M. Zuberi, MD8, Rima Nabbout, MD9, Kate Riney, MB BCh BAO, PhD10, Shikha Polega, PharmD11, Amélie Lothe, PhD12, Ronald Davis, MD13, Antonio Gil-Nagel, MD, PhD14
1University of Colorado, Children’s Hospital Colorado, Aurora, CO, USA, 2University of Melbourne, Austin Hospital and Royal Children’s Hospital, Melbourne, Victoria, Australia, 3Department of Paediatric Neurology, Antwerp University Hospital, Antwerp, Belgium, 4University of California San Francisco Weill Institute for Neurosciences, Benioff Children’s Hospital, San Francisco, CA, USA, 5Mayo Clinic, Department of Neurology, Rochester, MN, USA, 6Member of the European Reference Network EpiCARE; Department of Paediatric Neurology, University of Leuven, Leuven, Belgium, 7Pediatric Neurology and Neurogenetics Unit, Anna Meyer Children’s Hospital, University of Florence, Florence, Italy; IRCCS Fondazione Stella Maris, Pisa, Italy, 8Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom, 9Reference Centre for Rare Epilepsies, Hôpital Universitaire Necker-Enfants Malades, APHP, Member of EPICARE, Institut Imagine, Université Paris Cité, Paris, France, 10Neuroscience Unit, Queensland Children’s Hospital, South Brisbane, QLD, Australia; School of Clinical Medicine, University of Queensland, St Lucia, QLD, Australia, 11Zogenix, Inc. (now a part of UCB), Emeryville, CA, USA, 12Zogenix International, LTD (now a part of UCB), Maidenhead, UK, 13Neurology and Epilepsy Research Center, Orlando, FL, USA, 14Hospital Ruber Internacional, Madrid, Spain
Objective:
To evaluate fenfluramine treatment on drop seizure frequency (DSF) in adults and patients who were dose-capped at 26mg/day in a randomized clinical trial (RCT) or open-label extension (OLE) for Lennox-Gastaut syndrome (LGS).
Background:
Treatment for LGS is individualized and may evolve as the syndrome persists and changes into adulthood. Patients weighing ≥37.5kg (ie, most adults) had their doses capped at 26 mg/day and therefore received doses ≤0.7mg/kg/day.
Design/Methods:
After 4-weeks’ baseline in the RCT, LGS patients (2-35 years) were randomized to fenfluramine 0.7mg/kg/day (maximum, 26mg/day), fenfluramine 0.2mg/kg/day, or placebo for 2 weeks (titration) and 12 additional weeks. Eligible patients continuing into the OLE started on fenfluramine at 0.2mg/kg/day after a blinded 2-week taper. After 1 month, doses were titrated to effect/tolerability.
Results:
In the RCT, 76 adults (≥18-35 years) and 187 children/adolescents (2-17 years) were randomized to fenfluramine 0.7mg/kg/day (n=25 and 62, respectively), fenfluramine 0.2mg/kg/day (n=25 and 64), or placebo (n=26 and 61). Among both adults and children/adolescents, median DSF reduction from baseline was numerically greater in the 0.7mg/kg/day fenfluramine group (36.3%; P=0.0877 vs placebo [17.8%] and 20.3%; P=0.0106 vs placebo [4.8%]; nonparametric ANCOVA) and the 0.2mg/kg/day fenfluramine group (33.1%; P=0.1777 vs placebo [17.8%] and 7.2%; P=0.3268 vs placebo [4.8%]). Forty-seven patients weighed ≥37.5kg and were dose-capped at 26mg/day; median percentage reduction from baseline in DSF was greater than placebo (n=45) (35.3% vs 11.2%; P=0.0079 [ANCOVA]). In the OLE, 75% received ≤0.5mg/kg/day fenfluramine. Median reduction in DSF from baseline was 39.0% in adults (n=70) (P<0.0001, Wilcoxon signed rank test) and 25.6% in children/adolescents (n=171) (P=0.0037). Median percentage reductions in DSF were similar in patients weighing <37.5kg (28.3%; P=0.0127 [Wilcoxon signed rank test]) and ≥37.5kg (29.0%; P<0.0001).
Conclusions:
These data suggest that fenfluramine treatment results in effective, sustained DSF reduction in adults with LGS and patients weighing ≥37.5kg and dose-capped at 26mg/day.