Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial.

Autor:	Knight EMP; Epilepsy Center, Cleveland Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: pestane@ccf.org., Amin S; Pediatric Neurology, University Hospitals Bristol and Weston, Bristol, UK., Bahi-Buisson N; Pediatric Neurology, Necker Enfants Malades University Hospital, Paris, France., Benke TA; Department of Pediatrics and Neurology, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO, USA., Cross JH; UCL NIHR BRC Great Ormond Street Institute of Child Health, London, UK., Demarest ST; Department of Pediatrics and Neurology, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO, USA., Olson HE; Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA., Specchio N; Rare and Complex Epilepsy Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Fleming TR; Department of Biostatistics, University of Washington, Seattle, WA, USA., Aimetti AA; Marinus Pharmaceuticals, Radnor, PA, USA., Gasior M; Marinus Pharmaceuticals, Radnor, PA, USA., Devinsky O; New York University Langone Comprehensive Epilepsy Center, New York, NY, USA.
Jazyk:	angličtina
Zdroj:	The Lancet. Neurology [Lancet Neurol] 2022 May; Vol. 21 (5), pp. 417-427.
DOI:	10.1016/S1474-4422(22)00077-1
Abstrakt:	Background: CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy. Methods: In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2-21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT03572933, and the open-label extension phase is ongoing. Findings: Between June 25, 2018, and July 2, 2020, 114 patients were screened for eligibility, of whom 101 (median age 6 years [IQR 3 to 10]) were randomly assigned to receive either ganaxolone (n=50) or placebo (n=51). All patients received at least one dose of a study drug, but seizure frequency for one patient in the ganaxolone group was not recorded at baseline and so the primary endpoint was analysed in a population of 100 patients. There was a median percentage change in 28-day major motor seizure frequency of -30·7% (IQR -49·5 to -1·9) in the ganaxolone group and of -6·9% (-24·1 to 39·7) in the placebo group (p=0·0036). The Hodges-Lehmann estimate of median difference in responses to ganaxolone versus placebo was -27·1% (95% CI -47·9 to - 9·6). Treatment-emergent adverse events occurred in 43 (86%) of 50 patients in the ganaxolone group and in 45 (88%) of 51 patients in the placebo group. Somnolence, pyrexia, and upper respiratory tract infections occurred in at least 10% of patients in the ganaxolone group and more frequently than in the placebo group. Serious adverse events occurred in six (12%) patients in the ganaxolone group and in five (10%) patients in the placebo group. Two (4%) patients in the ganaxolone group and four (8%) patients in the placebo group discontinued the trial. There were no deaths in the double-blind phase. Interpretation: Ganaxolone significantly reduced the frequency of CDD-associated seizures compared with placebo and was generally well tolerated. Results from what is, to our knowledge, the first controlled trial in CDD suggest a potential treatment benefit for ganaxolone. Long-term treatment is being assessed in the ongoing open-label extension phase of this trial. Funding: Marinus Pharmaceuticals. Competing Interests: Declaration of interests EMPK has consulted for Marinus Pharmaceuticals, had no consulting relationship with Marinus Pharmaceuticals until after the completion of the double-blind phase of the current trial, and has participated in advisory boards for BioMarin and Zogenix. SA has received funding from GW Pharmaceuticals, Novartis, PTC Therapeutics, Boston Scientific, Nutricia, UCB, BioMarin, LivaNova, Medtronic, Desitin, Ipsen, CDKL5 UK, TSA, and the National Institute for Health Research. NB-B has consulted for Roche, LivaNova, and PTC Therapeutics, and has received funding from GW Pharmaceuticals. TAB has consulted for Taysha, Alcyone, Novartis/AveXis, Ovid, GW Pharmaceuticals, the International Rett Syndrome Foundation, Takeda, Ultragenyx, and Marinus Pharmaceuticals; has participated in clinical trials with Acadia, Ovid, GW Pharmaceuticals, Marinus Pharmaceuticals, and the Rett Syndrome Research Trust; and has received research funding from the National Institutes of Health, the International Foundation for CDKL5 Research, Rocky Mountain Rett Association, the GRIN2B Foundation, and Mallinckrodt (all remuneration has been made to his department). JHC has acted as an investigator for studies with GW Pharmaceuticals, Stoke Therapeutics, Ovid, Zogenix, and Vitaflo and for the current trial with Marinus Pharmaceuticals; has been a speaker and participated on advisory boards for Zogenix, Biocodex, UCB, and Nutricia (all remuneration has been paid to her department); holds an endowed chair at University College London Great Ormond Street Institute of Child Health (London, UK); and declares grants from the National Institute for Health Research, the Engineering and Physical Sciences Research Council, Great Ormond Street Hospital Children's Charity, Epilepsy Research United Kingdom, the Waterloo Foundation, and the National Institute of Health Research Biomedical Research Centre at Great Ormond Street Hospital. STD has consulted for Taysha, Neurogene, Ovid, and Marinus Pharmaceuticals; has received speaker honoraria from BioMarin and Marinus Pharmaceuticals; has received funding from the National Institutes of Health, the International Foundation for CDKL5 Research, and Mila's Miracle Foundation; and serves on advisory boards for the non-profit foundations SLC6A1 Connect, FamilieSCN2A, and Ring 14 USA. HEO has consulted for Takeda, Ovid, Zogenix, the FOXG1 Research Foundation, and Marinus Pharmaceuticals; has served as site principal investigator for a trial with Ovid and for the current trial with Marinus Pharmaceuticals; and has funding from the National Institute of Neurological Disorders and Stroke, the Loulou Foundation, the Manton Center for Rare Disease Research, and the International Foundation for CDKL5 Research for research on CDD. NS has served on scientific advisory boards for GW Pharmaceuticals, BioMarin, Arvelle, Takeda, and Marinus Pharmaceuticals; has received speaker honoraria from Eisai, BioMarin, LivaNova, and Sanofi; has served as an investigator for Zogenix, BioMarin, UCB, Roche, and Marinus Pharmaceuticals; and has received support for attending meetings from LivaNova. TRF received consulting fees from Marinus Pharmaceuticals for service on the scientific steering committee overseeing the design, conduct, and analysis of trials of ganaxolone in CDKL5-deficient epileptic encephalopathy and in protocadherin-19-related epilepsy. AAA is a salaried employee of Marinus Pharmaceuticals and owns stock in the company. MG is a salaried employee of Marinus Pharmaceuticals and owns stock in the company. OD receives grant support from the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, the Multidisciplinary University Research Initiative, the Centers for Disease Control and Prevention, and the National Science Foundation; has equity, compensation, or both from Tilray, Receptor Life Sciences, Q-State Biosciences, Tevard, Empatica, Papa & Barkley, Rettco, Silver Spike, and California Cannabis Enterprises; has received consulting fees from GW Pharmaceuticals, BridgeBio, Ultragenyx, Xenon, and Marinus Pharmaceuticals; has received honoraria from Medscape; has multiple patents for the use of cannabis but all financial benefits have been waived; has received royalties for the book Epilepsy in Children; and serves on the boards of FACES and Next for Autism. (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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