Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox–Gastaut syndrome: Interim analysis of an open‐label extension study
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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.
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The open-label extension phase of this study, in which 142 patients completed their final visit after 12 months, confirmed GTCS to be the most responsive seizure type, with median reductions over the entire extension period of 48.8%, whereas tonic seizures reduced by 35.8%.
“The open-label extension phase of this study, in which 142 patients completed their final visit after 12 months 203 , confirmed GTCS to be the most responsive seizure type, with median reductions over the entire extension period of 48.8%, whereas tonic seizures reduced by 35.8%.”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [203]
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Developmental and epileptic encephalopathies
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- Authors
- Knupp, K. G., Scheffer, I. E., Ceulemans, B., Sullivan, J., Nickels, K. C., Lagae, L., Guerrini, R., Zuberi, S. M., Nabbout, R., Riney, K., Agarwal, A., Lock, M., Dai, D., Farfel, G. M., Galer, B. S., Gammaitoni, A. R., Polega, S., Davis, R., & Gil‐Nagel, A.
- Affiliations
- Children's Hospital Colorado (US)
- Royal Children's Hospital (AU)
- Antwerp University Hospital (BE)
- University of California, San Francisco (US)
- Mayo Clinic (US)
- KU Leuven (BE)
- Meyer Children's Hospital (IT)
- Royal Hospital for Children (GB)
- Hôpital Necker-Enfants Malades (FR)
- The University of Queensland (AU)
- Zogenix (United States) (US)
- Syneos Health (United States) (US)
- Neurology and Epilepsy Research Center Orlando Florida USA
- Ruber International Hospital Madrid Spain
- Corresponding author
- Polega, Shikha
- ORCID
- Venue
- Epilepsia
- Publisher
- Wiley
- Published
- 2022-11-09
- Volume
- 64
- Issue
- 1
- Pages
- 139-151
- ISSN
- 0013-9580 (ISSN-L)
- 1528-1167
- PMC
- PMC10099582
- OpenAlex
- W4301594771
- Cited by
- 55
- References
- 34
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 14 · 2023: 7 · 2022: 3
- FWCI
- 7.17
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-05-30)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Epilepsia (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, cc-by-nc)
- Florence Research (University of Florence) (submittedVersion, cc-by-nc)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc)
- Funders
- Zogenix
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Health Sciences › Medicine › Physiology › Diet and metabolism studies
- Keywords
- fenfluramine, Lennox-Gastaut syndrome, drop seizures, seizure frequency reduction, open-label extension, long-term safety, antiepileptic drugs, generalized tonic-clonic seizures, tonic seizures, treatment-emergent adverse events, pediatric and adult patients, drug repurposing
- MeSH terms
- COVID-19, Adolescent, Adult, Anticonvulsants, Child, Fenfluramine, Humans, Seizures, Treatment Outcome, Young Adult, Lennox Gastaut Syndrome
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