Fenfluramine Treatment Is Associated With Improvement in Everyday Executive Function in Adults With Lennox-Gastaut Syndrome: Post-Hoc Analysis of Dose Effects From a Phase 3 Trial Rationale
Abstract number :
3.411
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2022
Submission ID :
2232947
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:28 AM
Authors :
Kim I. Bishop, PhD – President, Global Pharma Consultancy, LLC; Peter Isquith, PhD, ABPdN – Boston Children's Hospital, Harvard Medical School; Kelly Knupp, MD, MSCS, FAES – Children’s Hospital Colorado, University of Colorado Anschutz Medical Campus; Joseph Sullivan, MD – University of California San Francisco, Benioff Children’s Hospital; Rima Nabbout, MD – Centre de Référence Epilepsies Rares – Hôpital Universitaire Necker-Enfants Malades; Antonio Gil-Nagel, MD, PhD – Hospital Ruber Internacional; Ingrid Scheffer, PhD – University of Melbourne, Austin Hospital and Royal Children’s Hospital, Florey Institute and Murdoch Children’s Research Institute; Stéphane Auvin, MD, PhD – Robert Debré University Hospital, APHP, Université de Paris; J. Helen Cross, PhD – UCL NIHR BRC Great Ormond Street Institute of Child Health; Renzo Guerrini, MD, FRCP – Anna Meyer Children's Hospital, University of Florence; Robert Roth, PhD – Dartmouth-Hitchcock Medical Center; Gerald Gioia, PhD – Children’s National Health System; Amélie Lothe, PhD – Zogenix International (now a part of UCB);Shikha Polega, PharmD – UCB
This is a Late Breaking abstract
Rationale: Fenfluramine (FFA) is approved in the US for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients ≥ 2 years of age. LGS-associated disorders exist beyond seizures, including executive function (EF) issues. EF is an important domain for caregivers and families of patients with LGS, who deal with the impact of impairments in regulation of behavior, emotion, and cognition on their daily lives. FFA-treated children and adolescents with LGS in a previous post-hoc analysis showed clinically meaningful improvement in everyday EF. Here, we examine the associations between placebo and two FFA dosages and clinically meaningful changes on everyday EF over 14 weeks from a phase 3 trial in adults with LGS.
Methods: Everyday EF was assessed by caregivers with the Behavior Rating Inventory of Executive Function®—Adult Version (BRIEF®-A) indexes/composite and scales. Clinically meaningful improvement and worsening were defined using Reliable Change Index (RCI) ≥ 90% and ≥ 80% certainty, respectively. Associations between treatment groups (placebo, FFA 0.2 mg/kg/day, and FFA 0.7 mg/kg/day) and the likelihood of clinically meaningful change were calculated using cross-tabulations and Somers’ d (p≤0.05); when significant, two-sided Fisher’s Exact pairwise comparisons were performed (p≤0.05).
Results: Data were analyzed for 57 adults with LGS aged 19-35 years (placebo, n=23; FFA 0.2mg/kg/day, n=18; FFA 0.7mg/kg/day, n=16). All described associations met the a priori threshold (p≤0.05). There were positive associations between treatment groups and the likelihood of clinically meaningful improvement in the two indexes (Behavior Regulation Index, BRI; Metacognition Index, MI) and the global executive composite (GEC; Figure 1). Higher-dose FFA showed a greater likelihood of clinically meaningful improvement than placebo in MI. There were positive associations between the treatment groups and the likelihood of clinically meaningful improvement in three of four scales that comprise BRI (Inhibit, Shift, Self-Monitor) and three of five scales that comprise MI (Initiate, Task Monitor, and Organization of Materials; Figure 2). Higher-dose FFA showed a greater likelihood of clinically meaningful improvement than placebo in the Inhibit, Initiate, Task Monitor, and Organization of Materials scales. Lower-dose FFA showed a greater likelihood of clinically meaningful improvement than placebo in the Shift scale. There were no significant associations between treatment groups and the likelihood of clinically meaningful worsening.
Conclusions: FFA was associated with clinically meaningful improvements in everyday EF in adults with LGS over a relatively short treatment period. Higher-dose FFA showed a greater likelihood of clinically meaningful improvement in everyday cognitive regulation, driven by improvements in initiating, task monitoring, and organizing materials and environment. These data suggest that treatment with FFA initiated in adulthood also confers benefits in everyday EF.
Funding: UCB
Anti-seizure Medications