Authors :
Presenting Author: Kelly Knupp, MD, MSCS, FAES – University of Colorado, Children’s Hospital Colorado
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
Joseph Sullivan, MD – University of California San Francisco Weill Institute for Neurosciences
Sameer Zuberi, MBChB, MD – Paediatric Neurosciences Research Group, Royal Hospital for Children
Katherine Nickels, MD, FAAN, FAES – Mayo Clinic
Lieven Lagae, MD, PhD, FRCP – Member of the European Reference Network EpiCARE, University of Leuven
Renzo Guerrini, MD, FRCP, FAES – Meyer Children’s Hospital IRCCS, and University of Florence
James Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES – LeBonheur Children’s Hospital
Berten Ceulemans, MD, PhD – University of Antwerp
Patrick Healy, MS – UCB, Inc.
Mélanie Langlois, PhD – UCB Pharma S.A.
Jayne Abraham, PhD – UCB Pharma, Inc.
Amélie Lothe, PhD – UCB Pharma S.A.
Antonio Gil-Nagel, MD, PhD – Hospital Ruber Internacional
Rationale: Various factors contribute to severity of disease in Lennox-Gastaut syndrome (LGS), but high seizure frequency and specifically seizures associated with a fall increase the risk of injury, with downstream impacts of increased healthcare related costs and decreased quality of life. In this post-hoc analysis, baseline frequency of seizures associated with a fall was used as a surrogate marker of disease severity to evaluate efficacy and safety of fenfluramine (FFA) across a spectrum of patients with LGS who participated in the FFA randomized controlled trial (RCT).
Methods: In the FFA LGS 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. After a 2-week titration period, patients were maintained on their randomized dose for an additional 12 weeks. For this analysis, baseline characteristics were reported by quartiles (quartile 1 [Q1], quartile 2 [Q2], quartile 3 [Q3], and quartile 4 [Q4]) of baseline frequency of seizures associated with a fall. Descriptive statistics were used for the median change from baseline in frequency of seizures associated with a fall, ratings of improvement on Clinical Global Impression-Improvement (CGI-I) scale by investigator and caregiver at last visit, and incidence of treatment-emergent adverse event (TEAE) occurring in ≥10% of patients grouped by quartiles.
Results: Baseline characteristics for the treatment (FFA 0.2 mg/kg/day [n=89], FFA 0.7 mg/kg/day [n=87]) and placebo (n=87) groups are reported in
Table 1. For this analysis, number of seizures associated with a fall per quartile were: Q1: 2-34 seizures/28 days, Q2: 35-76 seizures/28 days, Q3: 77-175 seizures/28 days, Q4: >175 seizures/28 days. Throughout the 14 weeks of treatment, median percent change from baseline in frequency of seizures associated with a fall for placebo, FFA 0.2 mg/kg/day, and FFA 0.7 mg/kg/day, respectively, were as follows:
Q1: 7.6%, -39.1%, -27.7%; Q2: -15.7%, -8.8%, -31.6%; Q3: -21.3%, -33.1%, -36.3%; Q4: -11.2%, -7.7%, -13.5%. Results of the CGI-I ratings of improvement and clinically meaningful improvement by investigators and caregivers at last visit are described in
Table 2. In each of the four quartiles, decreased appetite and fatigue occurred in ≥10% of patients in the FFA 0.7 mg/kg/day group. Additional analyses will describe impact on generalized tonic-clonic seizure (GTCS) by baseline GTCS frequency.
Conclusions: In this post-hoc analysis, greater median percent reductions in seizures associated with a fall were observed in all quartiles when patients were treated with FFA 0.7 mg/kg/day compared with placebo. Additionally, ratings on CGI-I suggested that both caregivers and investigators observed clinically meaningful improvement after treatment with FFA regardless of baseline disease severity. Both the lower dose and higher dose of FFA were well-tolerated by patients with LGS.
Funding: UCB Pharma