TY - JOUR
T1 - Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox–Gastaut syndrome
T2 - Interim analysis of an open-label extension study
AU - Knupp, Kelly G.
AU - Scheffer, Ingrid E.
AU - Ceulemans, Berten
AU - Sullivan, Joseph
AU - Nickels, Katherine C.
AU - Lagae, Lieven
AU - Guerrini, Renzo
AU - Zuberi, Sameer M.
AU - Nabbout, Rima
AU - Riney, Kate
AU - Agarwal, Anupam
AU - Lock, Michael
AU - Dai, David
AU - Farfel, Gail M.
AU - Galer, Bradley S.
AU - Gammaitoni, Arnold R.
AU - Polega, Shikha
AU - Davis, Ronald
AU - Gil-Nagel, Antonio
N1 - Publisher Copyright:
© 2022 UCB and The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
PY - 2023/1
Y1 - 2023/1
N2 - Objective: This study was undertaken to evaluate the long-term safety and effectiveness of fenfluramine in patients with Lennox–Gastaut syndrome (LGS). Methods: 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.2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3-month intervals. The protocol-specified treatment duration was 12 months, but COVID-19-related delays resulted in 142 patients completing their final visit after 12 months. Results: As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2–4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was −28.6% over the entire OLE (n = 241) and −50.5% at Month 15 (n = 142, p <.0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was −45.9% (n = 192, p =.0038). Generalized tonic–clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p <.0001, n = 106) and 35.8% (p <.0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%–44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%–41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment-emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. Significance: Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long-term. Fenfluramine may provide an important long-term treatment option for LGS.
AB - Objective: This study was undertaken to evaluate the long-term safety and effectiveness of fenfluramine in patients with Lennox–Gastaut syndrome (LGS). Methods: 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.2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3-month intervals. The protocol-specified treatment duration was 12 months, but COVID-19-related delays resulted in 142 patients completing their final visit after 12 months. Results: As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2–4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was −28.6% over the entire OLE (n = 241) and −50.5% at Month 15 (n = 142, p <.0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was −45.9% (n = 192, p =.0038). Generalized tonic–clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p <.0001, n = 106) and 35.8% (p <.0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%–44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%–41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment-emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. Significance: Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long-term. Fenfluramine may provide an important long-term treatment option for LGS.
KW - Lennox–Gastaut syndrome
KW - developmental and epileptic encephalopathies
KW - fenfluramine
KW - long-term open-label extension
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U2 - 10.1111/epi.17431
DO - 10.1111/epi.17431
M3 - Article
C2 - 36196777
AN - SCOPUS:85141988094
SN - 0013-9580
VL - 64
SP - 139
EP - 151
JO - Epilepsia
JF - Epilepsia
IS - 1
ER -