Efficacy and Safety of N-Acetyl-l-Leucine in Children and Adults With GM2 Gangliosidoses.

Autor:	Martakis K; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland. kyriakos.martakis@paediat.med.uni-giessen.de., Claassen J; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland., Gascon-Bayari J; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland., Goldschagg N; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland., Hahn A; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland., Hassan A; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland., Hennig A; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland., Jones S; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland., Kay R; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland., Lau H; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland., Perlman S; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland., Sharma R; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland., Schneider S; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland., Bremova-Ertl T; From the Department of Pediatric Neurology (K.M., Andreas Hahn), University Children's Hospital (UKGM) and Medical Faculty, Justus Liebig University of Giessen, Giessen, Germany; Department of Pediatrics (K.M.), Medical Faculty and University Hospital, University of Cologne, Cologne, Germa; Department of Neurology (J.C.), Essen University Hospital, University of Duisburg-Essen, Germany; Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Germany; Department of Neurologic Diseases and Neurogenetics (J.G.-B.), Institut D'Investigació Biomèdica de Bellvitge, Barcelona, Spain; Department of Neurology (N.G., Anita Hennig, S.S.), Ludwig Maximilian University of Munich, Germany; Department of Neurology (Anhar Hassan), Mayo Clinic, Rochester, MN, United States; Willink Unit (S.J.), Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, United Kingdom; RK Statistics, Brook House, Mesne Lane, Bakewell DE45 1AL, United Kingdom 9. Division of Neurogenetics, New York University Langone, NY, United States; Department of Neurology (H.L.), New York University Langone School of Medicine, NY, United States; Department of Neurology (S.P.), University of California Los Angeles, CA, United States; Department of Adult Metabolic Medicine (R.S.), Salford Royal Foundation NHS Trust, United Kingdom; and Department of Neurology (T.B.-E.), University Hospital Bern (Inselspital), Switzerland.
Jazyk:	angličtina
Zdroj:	Neurology [Neurology] 2023 Mar 07; Vol. 100 (10), pp. e1072-e1083. Date of Electronic Publication: 2022 Dec 01.
DOI:	10.1212/WNL.0000000000201660
Abstrakt:	Background and Objectives: GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) are rare, autosomal recessive, neurodegenerative diseases with no available symptomatic or disease-modifying treatments. This clinical trial investigated N-acetyl-l-leucine (NALL), an orally administered, modified amino acid in pediatric (≥6 years) and adult patients with GM2 gangliosidoses. Methods: In this phase IIb, multinational, open-label, rater-blinded study (IB1001-202), male and female patients aged ≥6 years with a genetically confirmed diagnosis of GM2 gangliosidoses received orally administered NALL for a 6-week treatment period (4 g/d in patients ≥13 years, weight-tiered doses for patients 6-12 years), followed by a 6-week posttreatment washout period. For the primary Clinical Impression of Change in Severity analysis, patient performance on a predetermined primary anchor test (the 8-Meter Walk Test or the 9-Hole Peg Test) at baseline, after 6 weeks on NALL, and again after a 6-week washout period was videoed and evaluated centrally by blinded raters. Secondary outcomes included assessments of ataxia, clinical global impression, and quality of life. Results: Thirty patients between the age of 6 and 55 years were enrolled. Twenty-nine had an on-treatment assessment and were included in the primary modified intention-to-treat analysis. The study met its CI-CS primary end point (mean difference 0.71, SD = 2.09, 90% CI 0.00, 1.50, p = 0.039), as well as secondary measures of ataxia and global impression. NALL was safe and well tolerated, with no serious adverse reactions. Discussion: Treatment with NALL was associated with statistically significant and clinically relevant changes in functioning and quality of life in patients with GM2 gangliosidosis. NALL was safe and well tolerated, contributing to an overall favorable risk:benefit profile. NALL is a promising, easily administered (oral) therapeutic option for these rare, debilitating diseases with immense unmet medical needs. Trial Registration Information: The trial is registered with ClinicalTrials.gov (NCT03759665; registered on November 30, 2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled on June 7, 2019. Classification of Evidence: This study provides Class IV evidence that NALL improves outcomes for patients with GM2 gangliosidoses. (© 2022 American Academy of Neurology.)
Databáze:	MEDLINE
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