Fenfluramine in CDKL5 Deficiency Disorder: Primary Efficacy and Safety Results from a Phase 3, Randomized, Double-blind, Placebo-controlled Study
Brian Moseley1, Nicola Specchio2, Eric Marsh3, Orrin Devinsky4, Ángel Aledo-Serrano5, Domenica Immacolata Battaglia6, Rajsekar Rajaraman7, Karen Keough8, Ryoko Honda9, Renzo Guerrini10, Gia Melikishivili11, Sam Amin12, Amanda Jaksha13, Peter St. Wecker1, Brian Kilgallen1, Najla Dickson1, Joseph Sullivan14
1UCB, 2Bambino Gesù Children’s Hospital, IRCCS, Member of European Reference Network (ERN) EpiCARE; University Hospitals KU, 3Children's Hospital of Philadlephia; Perelman School of Medicine at the University of Pennsylvania, 4NYU Epilepsy Center, 5Neuroscience Institute, Vithas Madrid La Milagrosa University Hospital, 6Fondazione Policlinico Universitario Agostino Gemelli, IRCCS; Università Cattolica del Sacro Cuore, 7David Geffen School of Medicine; UCLA Mattel Children’s Hospital, 8Child Neurology and Consultants of Austin, 9Nagasaki Medical Center, Omura, 10Meyer Children's Hospital IRCCS, Member of the ERN EpiCARE; University of Florence, 11MediClubGeorgia Medical Center, 12University Hospitals Bristol and Weston, 13Patient caregiver, 14Weill Institute for Neurosciences and Benioff Children’s Hospital, University of California San Francisco
Objective:
To report primary results from a randomized placebo-controlled trial (RCT; NCT05064878) of fenfluramine in patients with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD).
Background:
CDD is an ultra-rare, drug-resistant, X-linked developmental and epileptic encephalopathy caused by CDKL5 gene mutations.
Design/Methods:
Eligible patients (1–35y) with confirmed/likely pathogenic CDKL5 mutation, clinical CDD diagnosis, and ≥4 countable motor seizures/week (caregiver-reported) were randomized to fenfluramine 0.7 mg/kg/day (max 26 mg/day) or placebo over 14 weeks (2-week titration [T], 12-week maintenance [M]). Primary efficacy endpoint was countable motor seizure frequency (CMSF) percentage change from baseline over T+M vs placebo.
Results:
Safety and modified intent-to-treat populations included 87 (fenfluramine, n=42; placebo, n=45) and 86 (fenfluramine, n=42; placebo, n=44) patients, respectively. Most patients (64%, fenfluramine; 62%, placebo) received ≥3 concomitant anti-seizure medications. Baseline median (range) CMSF was 44 (16–290), fenfluramine and 49 (0–1382), placebo. Significant differences in efficacy endpoints were observed with fenfluramine vs placebo (P<0.001): median percentage CMSF change was −47.6% vs −2.8%, providing an estimated median percentage difference of −52.7% (95% CI: −69.9 to −36.7); 45.2% vs 4.5% of patients achieved ≥50% CMSF reduction; 38.1% vs 6.8% demonstrated clinically meaningful improvement on Clinical Global Impression–Improvement scale (investigator-assessed). Median percentage change in generalized tonic-clonic seizure frequency from baseline: −61.5%, fenfluramine (n=14) vs −13.5%, placebo (n=18); P=0.099. Four patients (3, fenfluramine; 1, placebo) discontinued this RCT due to treatment-emergent adverse events (TEAEs). Of patients on fenfluramine, pyrexia, diarrhea, and somnolence were commonly reported (n=8 each, 19%). No new safety signals identified and no valvular heart disease or pulmonary arterial hypertension cases observed; no patients died in this RCT.
Conclusions:
In this study, fenfluramine provided significantly greater CMSF reduction in patients with CDD versus placebo; global functioning was improved and TEAEs were consistent with known fenfluramine safety profile. Fenfluramine may be a promising therapy for treating CDD-associated seizures.
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