Fenfluramine in CDKL5 Deficiency Disorder: Primary Efficacy and Safety Results From a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study
Abstract number :
2.429
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2025
Submission ID :
1341
Source :
www.aesnet.org
Presentation date :
12/7/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Nicola Specchio, MD, PhD, FRCP – Bambino Gesù Children’s Hospital, IRCCS, Member of the ERN EpiCARE; University Hospitals KU
Eric Marsh, MD, PhD – Children’s Hospital of Philadelphia; Perelman School of Medicine at the University of Pennsylvania
Orrin Devinsky, MD – NYU Comprehensive Epilepsy Center, NYU Langone Medical Center
Ángel Aledo-Serrano, MD, PhD – Neuroscience Institute, Vithas Madrid La Milagrosa University Hospital
Domenica Immacolata Battaglia, MD, PhD – Fondazione Policlinico Universitario Agostino Gemelli, IRCCS; Università Cattolica del Sacro Cuore
Rajsekar Rajaraman, MD – David Geffen School of Medicine; UCLA Mattel Children’s Hospital
Karen Keough, MD – Child Neurology and Consultants of Austin
Ryoko Honda, MD – NHO Nagasaki Medical Center
Renzo Guerrini, MD, FRCP – Meyer Children's Hospital IRCCS, Member of the ERN EpiCARE; University of Florence
Gia Melikishvili, MD – MediClubGeorgia Medical Center, Tbilisi, Georgia.
Sam Amin, MRCPCH, MSc, PhD – University Hospitals Bristol and Weston
Amanda Jaksha, BS – Patient caregiver
Brian Moseley, MD – UCB
Peter St. Wecker, PhD – UCB
Brian Kilgallen, MSc – UCB
Najla Dickson, MD – UCB
Joseph Sullivan, MD – Weill Institute for Neurosciences and Benioff Children’s Hospital, University of California San Francisco
Rationale: Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD), an X-linked disorder caused by CDKL5 gene mutations, is an ultra-rare, drug-resistant developmental and epileptic encephalopathy with early seizure onset. Here we report the primary efficacy and safety results from a randomized placebo-controlled trial (RCT) of fenfluramine (FFA) in patients (pts) with CDD (NCT05064878).
Methods: In this multicenter, phase 3 RCT, eligible pts were aged 1–35y with a confirmed or likely pathogenic CDKL5 mutation and a clinical CDD diagnosis, and ≥4 countable motor seizures/wk reported by caregivers. After a 4-wk baseline observation period, pts were randomized 1:1 to receive FFA 0.7 mg/kg/d (max 26 mg/d) or placebo (PBO) over a 2-wk titration (T) period, followed by a 12-wk maintenance (M) treatment period. The primary efficacy endpoint was the percentage change from baseline in countable motor seizure frequency (CMSF) over the 14-wk T+M period vs PBO. Key secondary endpoints were achievement of a ≥50% CMSF reduction from baseline during T+M; ratings of clinically meaningful improvement (‘much improved’ or ‘very much improved’) on Clinical Global Impression–Improvement (CGI–I) by investigators at end of T+M; and percentage change from baseline in monthly generalized tonic-clonic seizure (GTCS) frequency over T+M. Additional secondary efficacy and safety endpoints are reported. P values for the differences in CMSF and GTCS between FFA and PBO were calculated using nonparametric ANCOVA and the magnitude of differences were estimated using Hodges-Lehmann method. P values for the CGI–I rating comparisons were calculated with Fisher’s exact test.
Results: Analyzed safety population included 87 pts who received ≥1 dose of FFA (n=42) or PBO (n=45); modified intent-to-treat population comprised 86 pts with ≥1 wk of post-baseline seizure diary data (FFA, n=42; PBO, n=44). Baseline characteristics were balanced between the groups; 86% (36/42) and 89% (40/45) of pts who received FFA and PBO, respectively, were female. Mean±SD age (y) at baseline was 8.6±6.8 (range, 1–29) in the FFA group and 9.1±7.6 (range, 1–35) in the PBO group. Most pts (64%, FFA; 62%, PBO) received ≥3 concomitant anti-seizure medications. Baseline median (range) CMSF for pts in the FFA and PBO groups was 44 (16–290) and 49 (0–1382), respectively. Statistically significant differences in the primary and 2 key secondary efficacy endpoints were observed with FFA vs PBO (Table 1). Estimated median percentage difference between FFA and PBO in CMSF was −52.7% (95% CI: −69.9 to −36.7). Four pts (3, FFA; 1, PBO) discontinued this RCT due to a treatment emergent adverse event (TEAE; Table 2). Overall, no new safety signals were identified; no valvular heart disease or pulmonary arterial hypertension cases were reported and no pts died in this double-blind trial.
Conclusions: In this first RCT evaluating FFA in pts with CDD, FFA provided significantly greater reduction in CMSF compared with PBO and was generally well tolerated; TEAEs were consistent with the known safety profile of FFA in Dravet and Lennox-Gastaut syndromes. These data suggest that FFA may be a promising therapy for treating seizures in pts with CDD.
Funding: UCB.
Anti-seizure Medications