HPN Symposium

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Poster · Epilepsy & Seizure Disorders

Fenfluramine in CDKL5 deficiency disorder: primary efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study

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Nicola Specchio, MD, PhD, FRCP1,2, Eric Marsh, MD, PhD3,4, Orrin Devinsky, MD5, Ángel Aledo-Serrano, MD, PhD6, Domenica Immacolata Battaglia, MD, PhD7,8, Rajsekar Rajaraman, MD9,10, Karen Keough, MD11, Ryoko Honda12, Renzo Guerrini, MD, FRCP13,14, Gia Melikishvili, MD15, Sam Amin, MRCPCH, MSc, PhD16, Amanda Jaksha17, Brian Moseley, MD18, Peter St. Wecker, PhD19, Brian Kilgallen, MSc18, Najla Dickson, MD18, Joseph Sullivan, MD20

  1. 1 Bambino Gesù Children’s Hospital, IRCCS, Member of European Reference Network (ERN) EpiCARE, Rome, Italy
  2. 2 University Hospitals KU, Leuven, Belgium
  3. 3 Children’s Hospital of Philadelphia, Philadelphia, PA, USA
  4. 4 Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
  5. 5 NYU Comprehensive Epilepsy Center, NYU Langone Medical Center, New York, NY, USA
  6. 6 Neuroscience Institute, Vithas Madrid La Milagrosa University Hospital, Madrid, Spain
  7. 7 Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Roma, Italy
  8. 8 Università Cattolica del Sacro Cuore, Roma, Italy
  9. 9 David Geffen School of Medicine, Los Angeles, CA, USA
  10. 10 UCLA Mattel Children’s Hospital, Los Angeles, CA, USA
  11. 11 Child Neurology and Consultants of Austin, Austin, TX, USA
  12. 12 Nagasaki Medical Center, Omura, Nagasaki, Japan
  13. 13 Meyer Children's Hospital IRCCS, Member of the ERN EpiCARE, Florence, Italy
  14. 14 University of Florence, Florence, Italy
  15. 15 MediClubGeorgia Medical Center, Tbilisi, Georgia
  16. 16 University Hospitals Bristol and Weston, Bristol, United Kingdom
  17. 17 Patient caregiver, Denver, CO, USA
  18. 18 UCB, Morrisville, NC, USA
  19. 19 UCB, Emeryville, CA, USA
  20. 20 Weill Institute for Neurosciences and Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA, USA 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 with CDD (NCT05064878).

Methods: In this multicenter, phase 3 RCT, eligible patients were aged 1–35 years with a confirmed pathogenic or likely pathogenic CDKL5 mutation, a clinical CDD diagnosis, and ≥4 countable motor seizures/week reported by caregivers. After a 4-week baseline observation period, patients were randomized 1:1 to receive FFA 0.7 mg/kg/d (max 26 mg/d) or placebo (PBO) over a 2-week titration (T) period, followed by a 12-week maintenance (M) treatment period. The primary efficacy endpoint was the percentage change from baseline in countable motor seizure frequency (CMSF) over the 14-week 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: The analyzed safety population included 87 patients who received ≥1 dose of FFA (n=42) or PBO (n=45); the modified intent-to-treat population comprised 86 patients with ≥1 week 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 patients who received FFA and PBO, respectively, were female. Mean±SD age (years) 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 patients (64%, FFA; 62%, PBO) received ≥3 concomitant antiseizure medications. Baseline median (range) CMSF for patients 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 patients (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 patients died in this double-blind trial.

Conclusion: In this first RCT evaluating FFA in patients 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 syndrome and Lennox-Gastaut syndrome. These data suggest that FFA may be a promising therapy for treating seizures in patients with CDD. Funding: UCB-sponsored.