A Post-hoc Evaluation of Fenfluramine with or Without Vagus Nerve Stimulation in Lennox-gastaut Syndrome Clinical Trials
Abstract number :
1.336
Submission category :
4. Clinical Epilepsy / 4C. Clinical Treatments
Year :
2024
Submission ID :
1024
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Lieven Lagae, MD, PhD, FRCP – Member of the European Reference Network EpiCARE, University of Leuven
Kelly Knupp, MD, MSCS, FAES – University of Colorado, Children’s Hospital Colorado
Joseph Sullivan, MD – University of California San Francisco Weill Institute for Neurosciences
James Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES – LeBonheur Children’s Hospital
Rima Nabbout, MD, PhD – Member of European Reference Network EpiCARE, Reference Centre for Rare Epilepsies, Necker Enfants Malades Hospital, APHP, U 1163 Institut Imagine, Université Paris Cité
Ingrid Scheffer, MBBS, PhD, FRACP, FRS – University of Melbourne, Austin Hospital and Royal Children's Hospital, Florey and Murdoch Children’s Research Institutes
Renzo Guerrini, MD, FRCP, FAES – Meyer Children’s Hospital IRCCS, and University of Florence
Fawad Khan, MD – Ochsner Health
Michael Macken, MD – Northwestern University
Sameer Zuberi, MBChB, MD – Paediatric Neurosciences Research Group, Royal Hospital for Children
Antonio Gil-Nagel, MD, PhD – Hospital Ruber Internacional
Patrick Healy, MS – UCB, Inc.
Jayne Abraham, PhD – UCB Pharma, Inc.
Amélie Lothe, PhD – UCB Pharma S.A.
Nicola Specchio, MD, PhD – Bambino Gesu’ Children’s Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE
Rationale: Vagus nerve stimulation (VNS) is an adjunctive, nonpharmacological treatment indicated for patients with drug-resistant epilepsy that may reduce seizure burden in patients with Lennox-Gastaut syndrome (LGS). Since VNS and fenfluramine (FFA) are both associated with serotonergic mechanisms, we evaluated the impact on safety and efficacy in patients in the FFA randomized controlled trial (RCT) and open-label extension (OLE) study when patients were on FFA with VNS versus those without VNS.
Methods: In the 14-week FFA RCT (NCT03355209), patients were randomized to FFA 0.2 mg/kg/day or FFA 0.7 mg/kg/day (maximum 26 mg/day) or placebo. In the OLE study (NCT03355209), after completing the RCT, patients were transitioned to FFA 0.2 mg/kg/day for 1 month, then flexibly titrated to effect and tolerability. No change of VNS settings or concomitant anti-seizure medications (ASMs) were allowed during the RCT and the first 6 months of the OLE. For this post-hoc analysis, the following were evaluated according to use of concomitant VNS versus no VNS: median percent change from baseline in seizures (seizures associated with a fall and generalized tonic-clonic seizures, [GTCS]), responder analyses, and incidence of treatment-emergent adverse events (TEAEs). Descriptive analyses and Clopper-Pearson for confidence intervals were used.
Results: Of the 82 patients with concomitant VNS at baseline in the RCT, 32 were randomized to placebo and 50 to FFA; 181 patients were not on concomitant VNS. In the OLE, 80/241 patients were on FFA+VNS at RCT baseline (See Table). Baseline median number of seizures associated with a fall was higher in FFA treatment groups without concomitant VNS (See Table). Median percent reduction in seizures associated with a fall was similar across groups regardless of VNS use (See Figure). In the RCT, FFA+VNS led to greater reductions in GTCS than without VNS; conversely, in the OLE a higher median reduction in GTCS was observed when FFA was given without concomitant VNS (Figure). In combined FFA groups in the RCT, a greater proportion of patients achieved both ≥50% and ≥75% reduction in seizures associated with a fall when treated without VNS compared to patients on FFA+VNS (27.8% and 11.1% vs 24% and 4%). In the OLE, 32.9% and 13.7% of patients on FFA without VNS achieved ≥50% and ≥75% reduction in seizures associated with a fall, respectively, versus 27.5% and 7.5% of patients on FFA+VNS. Of the TEAEs reported in ≥10% of patients in the RCT and OLE, fatigue occurred more frequently in the patients on FFA+VNS versus those without VNS (RCT: 17.1% vs 11.6%; OLE: 18.8% vs 11.2%).
Conclusions: In this analysis, use of FFA in the LGS clinical trials was effective and safe irrespective of concomitant use of VNS. Further evaluation of VNS settings and duration of therapy may be needed, and larger studies would provide insight into the combined use of VNS and FFA. Additionally, an analysis of FFA use with other non-pharmacological treatments (eg, ketogenic diet) may be useful.
Funding: Funded by UCB Pharma
Clinical Epilepsy