Authors :
J Helen Cross, MD – UCL-Great Ormond Street Institute of Child Health; Great Ormond Street Hospital; Orrin Devinsky, MD – NYU Langone Medical Center; Antonio Gil-Nagel, MD PhD – Hospital Ruber Internacional; Berten Ceulemans, MD PhD – University of Antwerp; Lieven Lagae, MD PhD – University of Leuven; Kelly Knupp, MD MSCS FAES – Children’s Hospital Colorado; An-Sofie Schoonjans, MD PhD – University of Antwerp; Philippe Ryvlin, MD – University of Lausanne; Elizabeth Thiele, MD PhD – Massachusetts General Hospital; Rima Nabbout, MD PhD – Paris Descartes University; Amélie Lothe, PhD – Zogenix International (now a part of UCB); Shikha Polega, PharmD – Zogenix, Inc. (now a part of UCB
This is a Late Breaking abstractRationale: Sudden unexpected death in epilepsy (SUDEP) is a common cause of death in patients with developmental and epileptic encephalopathies (DEEs) and is a leading fear of parents and caregivers. Seizure refractoriness and frequent generalized tonic-clonic seizures (GTCS) are hallmarks of DEEs and are two major risk factors for SUDEP. Patients with 1-3 GTCS per year have up to a 16-fold greater risk of SUDEP. Fenfluramine (FFA) targets the serotonergic system and sigma-1 receptors and decreases GTCS frequency. An analysis of SUDEP rates in patients with Dravet syndrome (DS) found FFA-treated patients had a 5-fold lower SUDEP mortality rate when compared to historical controls. Beyond its labeled indications in DS and Lennox-Gastaut syndrome (LGS), FFA has also reduced seizure burden in other rare epilepsies. Here, we review publications regarding the effectiveness of FFA on GTCS in patients with rare epilepsy syndromes.
Methods: Reports of patients treated with FFA for seizures associated with rare epilepsy sundromes were identified and subsequently included if FFA was used for convulsive seizure control. The studies selected described a change in the frequency of GTCS, tonic-clonic seizures (TCS), or major motor seizures.
Case reports or studies where the reduction in GTCS or TCS was unclear were excluded. Initial FFA doses, duration of treatment (exposure) and reduction in GTCS are reported. Descriptive statistics were used for the analysis.
Results:
We included data from 13 studies: 4 randomized-controlled trials (RCTs), 4 observational studies, 4 open-label studies, and 1 case series (Table). A total of 561 patients were enrolled and treated with FFA for DS (n=360), LGS (n=176), Sunflower syndrome (n=10), CDKL5 deficiency disorder (n=6), SCN8A-related disorder (n=3), and other DEEs(n=6). Patients were generally initiated on 0.2 mg/kg/day FFA added to their baseline standard-of-care regimen and titrated per protocol or by physician discretion. Treatment duration (exposure) ranged from 14-15 weeks (RCTs), and up to 27 years. Overall, 396 (70.6%) patients were identified that experienced GTCS or TCS at baseline. In 3 studies, the reduction in GTCS or TCS was included as part of the overall seizure type evaluated. A reduction in frequency of GTCS or TCS was observed in most FFA-treated patients. In 7 studies (including the 4 RCTs), the median percent reduction in GTCS ranged from 45.7 to 90.8%. Among 8 studies providing data, 7 reported at least half of the patients experienced ≥ 75% reduction in GTCS (or TCS) frequency; five studies reported that more than half of patients were GTCS-free after FFA treatment.
Conclusions: These results indicate that FFA led to a clinically significant reduction in GTCS (or TCS) frequency in patients with rare epilepsy syndromes, suggesting it may also reduce SUDEP rates in these disorders. Further research is needed to determine the impact of FFA on SUDEP in those patient populations.
Funding: Funded by Zogenix, Inc. (now a part of UCB)