Impact of Fenfluramine on Convulsive Seizure Frequency in Dose-Capped Patients With Dravet Syndrome
Rima Nabbout1, Kelly Knupp2, Lieven Lagae3, J Helen Cross4, Joseph Sullivan5, Antonio Gil-Nagel6, Renzo Guerrini7, Adam Strzelczyk8, Mélanie Langlois9, Patrick Healy9, Amélie Lothe9, Ingrid Scheffer10
1Member of the European Reference Network EpiCARE, Reference Centre for Rare Epilepsies, Hôpital Universitaire Necker-Enfants Malades, APHP, Institut Imagine, Université Paris Cité, 2University of Colorado, Children's Hospital Colorado, 3Member of the European Reference Network EpiCARE; University of Leuven, 4UCL NIHR BRC Great Ormond Street Institute of Child Health, Great Ormond Street Hospital, 5University of California San Francisco Weill Institute for Neurosciences, Benioff Children’s Hospital, 6Hospital Ruber Internacional, 7IRCCS Fondazione Stella Maris, Pisa; Pediatric Neurology and Neurogenetics Unit, Anna Meyer Children’s Hospital, University of Florence, 8Goethe University Frankfurt, Epilepsy Center Frankfurt Rhine-Main & University Hospital Frankfurt, 9UCB, 10University of Melbourne, Austin Hospital and Royal Children’s Hospital, Florey and Murdoch Children’s Research Institutes
Objective:
To determine fenfluramine effectiveness in the treatment of convulsive seizures in dose-capped patients with Dravet syndrome (DS).
Background:
DS is a rare treatment-resistant developmental and epileptic encephalopathy characterized by seizure onset within the first year of life and developmental delay. Fenfluramine is approved in the United States, European Union, United Kingdom, Israel, and Japan for seizures associated with DS in patients ≥2 years old. Weight-based fenfluramine dosing and daily fenfluramine maximum dose guidelines may cap heavier patients below their therapeutic dose.
Design/Methods:
Patients with DS who completed any of three randomized controlled trials (RCTs) were eligible to enroll in a 36-month open-label extension (OLE; NCT02823145). At RCT completion, patients were re-initiated with fenfluramine 0.2 mg/kg/day for 4 weeks, and then titrated to effect and tolerability with a maximum dose of 0.7 mg/kg/day (maximum 26 mg/day) or 0.4 mg/kg/day (maximum 17 mg/day) with concomitant stiripentol. Patients weighing ≥37.5 kg were potentially dose-capped if the maximum daily dose was reached before reaching 0.7 mg/kg/day (or 0.4 mg/kg/day with stiripentol). In this post-hoc analysis, median percentage change in monthly convulsive seizure frequency (MCSF) from RCT baseline to OLE Month 2 to end-of-study (EOS) was measured.
Results:
Of 374 patients who received fenfluramine, 93 (24.9%) were dose-capped. Mean baseline age (SD) was 13.4 (2.9) years old (range, 7-18 years). Mean (SD) baseline bodyweight was 49.9 (13.2) kg (range, 28.3-99.7 kg). Median percent change in MCSF from Month 2 to EOS was -69.06 (range, -100 to 285.4), -62.80 (range, -100 to 247.5), and -61.56 (range, -99.2 to 90.8) in patients weighing <37.5 kg, ≥37.5 kg, and ≥37.5 kg + dose-capped, respectively (nominal Wilcoxon signed rank P<0.0001 for each).
Conclusions:
Patients weighing ≥37.5 kg and receiving the maximum daily dose of fenfluramine (i.e., dose-capped) experienced similar MCSF change from RCT baseline as patients who were not dose-capped.
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