Final analysis from an open-label extension study of fenfluramine for the treatment of seizures in Lennox-Gastaut syndrome: long-term impact on patients and caregivers

Kelly G Knupp¹, Ingrid E Scheffer², An-Sofie Schoonjans³, Joseph Sullivan⁴, Lieven Lagae⁵, Stéphane Auvin⁶, Elizabeth A Thiele⁷, Renzo Guerrini⁸, Sameer M Zuberi⁹, Rima Nabbout¹⁰, Kate Riney¹¹, Katherine C Nickels¹², Ronald Davis¹³, Michael D Lock¹⁴, David Dai¹⁵, Timothy Minh¹⁶, Rebecca Zhang Roper¹⁷, Najla Dickson¹⁸, Mélanie Langlois¹⁹, Amélie Lothe²⁰, Antonio Gil-Nagel²¹

Affiliations

¹ University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Electronic address: Kelly.knupp@childrenscolorado.org.
² University of Melbourne, Austin Health, Heidelberg, Melbourne, Victoria, Australia; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia; Murdoch Children's Research Institute, Parkville, Victoria, Australia. Electronic address: i.scheffer@unimelb.edu.au.
³ University Hospital Antwerp, Antwerp, Belgium. Electronic address: an-sofie.schoonjans@uza.be.
⁴ Weill Institute for Neurosciences and Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA. Electronic address: joseph.sullivan@UCSF.edu.
⁵ University of Leuven, Leuven, Belgium; Leuven Childhood Epilepsy Center, Leuven Brain Institute, UZ Leuven, Member of the European Reference Network (ERN) EpiCARE, Leuven, Belgium. Electronic address: lieven.lagae@uzleuven.be.
⁶ AP-HP, Reference Center for Rare Epilepsies, Member of the ERN EpiCARE, Hôpital Universitaire Robert Debré, Paris, France; Institut Hospitalo-Universitaire Robert-Debré du Cerveau de l'Enfant, Paris, France; Université Paris-Cité, INSERM NeuroDiderot, Paris, France; Institut Universitaire de France (IUF), Paris, France. Electronic address: stephane.auvin@aphp.fr.
⁷ Massachusetts General Hospital, Boston, MA, USA. Electronic address: ethiele@mgh.harvard.edu.
⁸ Meyer Children's Hospital IRCCS, Member of the ERN EpiCARE, Florence, Italy; University of Florence, Florence, Italy. Electronic address: renzo.guerrini@unifi.it.
⁹ Paediatric Neurosciences Research Group, School of Health and Wellbeing, University of Glasgow, Glasgow, UK; Royal Hospital for Children, Glasgow, UK; Queen Elizabeth University Hospital, Member of the ERN EpiCARE, Glasgow, UK. Electronic address: sameer.zuberi@gla.ac.uk.
¹⁰ Reference Centre for Rare Epilepsies, Necker Enfants Malades Hospital, APHP, Member of the ERN EpiCARE, Paris, France; Institut Imagine, U 1163, Paris, France; Université Paris Cité, Paris, France. Electronic address: rima.nabbout@aphp.fr.
¹¹ The University of Queensland, St Lucia, QLD 4067, Australia; Queensland Children's Hospital, South Brisbane, QLD 4101, Australia; Children's Health Queensland, Queensland Hospital and Health Service, South Brisbane, QLD 4101, Australia. Electronic address: kate.riney@health.qld.gov.au.
¹² Mayo Clinic, Rochester, MN, USA. Electronic address: nickels.katherine@mayo.edu.
¹³ Neurology and Epilepsy Research Center, Orlando, FL, USA. Electronic address: majrdavis@aol.com.
¹⁴ Independent Statistical Consultant, Haiku, HI, USA. Electronic address: mike@lockstats.com.
¹⁵ Syneos Health, Morrisville, NC, USA. Electronic address: david.dai@syneoshealth.com.
¹⁶ UCB, Morrisville, NC, USA. Electronic address: Timothy.minh@ucb.com.
¹⁷ UCB, Slough, UK. Electronic address: rebecca.zhangroper@ucb.com.
¹⁸ UCB, Morrisville, NC, USA. Electronic address: najla.dickson@ucb.com.
¹⁹ UCB, Colombes, France. Electronic address: melanie.langlois@ucb.com.
²⁰ UCB, Colombes, France. Electronic address: amelie.lothe@ucb.com.
²¹ Hospital Ruber Internacional, Madrid, Spain. Electronic address: agnagel@neurologiaclinica.es.

PMID: 41075528
DOI: 10.1016/j.yebeh.2025.110753

Free article

Final analysis from an open-label extension study of fenfluramine for the treatment of seizures in Lennox-Gastaut syndrome: long-term impact on patients and caregivers

Kelly G Knupp et al. Epilepsy Behav. 2025.

Free article

. 2025 Oct 10:173:110753.

doi: 10.1016/j.yebeh.2025.110753. Online ahead of print.

Authors

Affiliations

¹ University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Electronic address: Kelly.knupp@childrenscolorado.org.
² University of Melbourne, Austin Health, Heidelberg, Melbourne, Victoria, Australia; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia; Murdoch Children's Research Institute, Parkville, Victoria, Australia. Electronic address: i.scheffer@unimelb.edu.au.
³ University Hospital Antwerp, Antwerp, Belgium. Electronic address: an-sofie.schoonjans@uza.be.
⁴ Weill Institute for Neurosciences and Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA. Electronic address: joseph.sullivan@UCSF.edu.
⁵ University of Leuven, Leuven, Belgium; Leuven Childhood Epilepsy Center, Leuven Brain Institute, UZ Leuven, Member of the European Reference Network (ERN) EpiCARE, Leuven, Belgium. Electronic address: lieven.lagae@uzleuven.be.
⁶ AP-HP, Reference Center for Rare Epilepsies, Member of the ERN EpiCARE, Hôpital Universitaire Robert Debré, Paris, France; Institut Hospitalo-Universitaire Robert-Debré du Cerveau de l'Enfant, Paris, France; Université Paris-Cité, INSERM NeuroDiderot, Paris, France; Institut Universitaire de France (IUF), Paris, France. Electronic address: stephane.auvin@aphp.fr.
⁷ Massachusetts General Hospital, Boston, MA, USA. Electronic address: ethiele@mgh.harvard.edu.
⁸ Meyer Children's Hospital IRCCS, Member of the ERN EpiCARE, Florence, Italy; University of Florence, Florence, Italy. Electronic address: renzo.guerrini@unifi.it.
⁹ Paediatric Neurosciences Research Group, School of Health and Wellbeing, University of Glasgow, Glasgow, UK; Royal Hospital for Children, Glasgow, UK; Queen Elizabeth University Hospital, Member of the ERN EpiCARE, Glasgow, UK. Electronic address: sameer.zuberi@gla.ac.uk.
¹⁰ Reference Centre for Rare Epilepsies, Necker Enfants Malades Hospital, APHP, Member of the ERN EpiCARE, Paris, France; Institut Imagine, U 1163, Paris, France; Université Paris Cité, Paris, France. Electronic address: rima.nabbout@aphp.fr.
¹¹ The University of Queensland, St Lucia, QLD 4067, Australia; Queensland Children's Hospital, South Brisbane, QLD 4101, Australia; Children's Health Queensland, Queensland Hospital and Health Service, South Brisbane, QLD 4101, Australia. Electronic address: kate.riney@health.qld.gov.au.
¹² Mayo Clinic, Rochester, MN, USA. Electronic address: nickels.katherine@mayo.edu.
¹³ Neurology and Epilepsy Research Center, Orlando, FL, USA. Electronic address: majrdavis@aol.com.
¹⁴ Independent Statistical Consultant, Haiku, HI, USA. Electronic address: mike@lockstats.com.
¹⁵ Syneos Health, Morrisville, NC, USA. Electronic address: david.dai@syneoshealth.com.
¹⁶ UCB, Morrisville, NC, USA. Electronic address: Timothy.minh@ucb.com.
¹⁷ UCB, Slough, UK. Electronic address: rebecca.zhangroper@ucb.com.
¹⁸ UCB, Morrisville, NC, USA. Electronic address: najla.dickson@ucb.com.
¹⁹ UCB, Colombes, France. Electronic address: melanie.langlois@ucb.com.
²⁰ UCB, Colombes, France. Electronic address: amelie.lothe@ucb.com.
²¹ Hospital Ruber Internacional, Madrid, Spain. Electronic address: agnagel@neurologiaclinica.es.

PMID: 41075528
DOI: 10.1016/j.yebeh.2025.110753

Abstract

Objective: To describe long-term safety and effectiveness of fenfluramine in pediatric and adult patients with Lennox-Gastaut syndrome (LGS) from the final analysis of an open-label extension (OLE) study.

Methods: Patients (aged 2-35y) who participated in the randomized controlled trial (RCT) were eligible to continue in this OLE (NCT03355209). Fenfluramine 0.2 mg/kg/day was initiated; after one month, titration up to 0.7 mg/kg/day (26 mg/day maximum) was allowed. Key endpoints: incidence of treatment-emergent adverse events (TEAEs), median percentage change from RCT baseline in frequency of seizures associated with a fall, improvement by caregivers and investigators on Clinical Global Impression-Improvement (CGI-I), change from baseline in Quality of Life in Childhood Epilepsy Questionnaire scores, and Hospital Anxiety and Depression Scale (HADS) in parents/caregivers.

Results: 247 patients enrolled: 158 (64.0 %) patients completed this OLE. Mean ± SD age, 14.3 ± 7.6y; median fenfluramine exposure, 364d (range, 19-537); mean ± SD fenfluramine daily dose, 0.4 ± 0.1 mg/kg/day. TEAEs in ≥10 % of patients: decreased appetite, fatigue, nasopharyngitis, seizure, pyrexia; no valvular heart disease or pulmonary arterial hypertension cases. Median change in frequency of seizures associated with a fall from Month 2 to end of study: -31.1 % (n = 240; P < 0.0001); pediatric: -27.6 % (n = 170; P = 0.0005), adult: -40.0 % (n = 70; P < 0.0001). On last-visit CGI-I, caregivers and investigators rated 59.9 % and 57.0 % of patients as improved, respectively. At Month 12, mean overall patient quality of life and caregiver anxiety on HADS significantly improved from baseline.

Significance: These results support the long-term safety and effectiveness of fenfluramine in patients with LGS, with no new safety signals identified, and sustained reductions in seizures and improvement in global functioning observed.

Keywords: Fenfluramine; Lennox-Gastaut syndrome; Long-term open-label extension.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

LinkOut - more resources

Full Text Sources
- ClinicalKey
- Elsevier Science

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Final analysis from an open-label extension study of fenfluramine for the treatment of seizures in Lennox-Gastaut syndrome: long-term impact on patients and caregivers

Affiliations

Final analysis from an open-label extension study of fenfluramine for the treatment of seizures in Lennox-Gastaut syndrome: long-term impact on patients and caregivers

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources