Efficacy and safety of N-acetyl-L-leucine in Niemann-Pick disease type C.
Acetyl-leucine
Ataxia
Lysosomal storage disorder
Niemann–Pick disease type C
Symptomatic therapy
Journal
Journal of neurology
ISSN: 1432-1459
Titre abrégé: J Neurol
Pays: Germany
ID NLM: 0423161
Informations de publication
Date de publication:
Mar 2022
Mar 2022
Historique:
received:
06
05
2021
accepted:
13
07
2021
revised:
12
07
2021
pubmed:
14
8
2021
medline:
23
2
2022
entrez:
13
8
2021
Statut:
ppublish
Résumé
To investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann-Pick disease type C (NPC) patients. In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments. 33 subjects aged 7-64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred. NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. CLINICALTRIALS. NCT03759639.
Identifiants
pubmed: 34387740
doi: 10.1007/s00415-021-10717-0
pii: 10.1007/s00415-021-10717-0
pmc: PMC8361244
doi:
Substances chimiques
Leucine
GMW67QNF9C
acetylleucine
K76S41V71X
Banques de données
ClinicalTrials.gov
['NCT03759639']
Types de publication
Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
1651-1662Informations de copyright
© 2021. The Author(s).
Références
Geberhiwot T, Moro A, Dardis A et al (2018) Consensus clinical management guidelines for Niemann-Pick disease type C. Orphanet J Rare Dis 13:50
doi: 10.1186/s13023-018-0785-7
Vanier MT, Millat G (2003) Niemann–Pick disease type C. Clin Genet 64:269–281
doi: 10.1034/j.1399-0004.2003.00147.x
Bremova T, Malinová V, Amraoui Y et al (2015) Acetyl-DL-leucine in Niemann–Pick type C: a case series. Neurology 85:1368–1375
doi: 10.1212/WNL.0000000000002041
Cortina-Borja M, Te Vruchte D, Mengel E et al (2018) Annual severity increment score as a tool for stratifying patients with Niemann–Pick disease type C and for recruitment to clinical trials. Orphanet J Rare Dis 13:143
doi: 10.1186/s13023-018-0880-9
Kaya E, Smith DA, Smith C et al (2020) Acetyl-leucine slows disease progression in lysosomal storage disorders. Brain Commun. https://doi.org/10.1093/braincomms/fcaa148
doi: 10.1093/braincomms/fcaa148
pubmed: 33738443
pmcid: 7954382
Churchill GC, Strupp M, Galione A, Platt FM (2020) Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance. PLoS ONE 15:e0229585
doi: 10.1371/journal.pone.0229585
Fields T, Patterson M, Bremova-Ertl T, Belcher G, Billington I, Churchill GC, Davis W, Evans W, Flint S Galione A, Granzer U, Greenfield J, Karl R, Kay R, Lewi D, Mathieson T, Meyer T, Pangonis D, Platt FM, Tsang Verburg C, Factor M, Strupp M (2021) A master protocol to investigate a novel therapy acetyl-l-leucine for three ultra-rare neurodegenerative diseases: niemann-Pick type C the GM2 gangliosidoses and ataxia telangiectasia. Trials 22(1). https://doi.org/10.1186/s13063-020-05009-3
Patterson MC, Clayton P, Gissen P et al (2017) Recommendations for the detection and diagnosis of Niemann–Pick disease type C: an update. Neurol Clin Pract 7:499–511
doi: 10.1212/CPJ.0000000000000399
Iturriaga C, Pineda M, Fernández-Valero EM, Vanier MT, Coll MJ (2006) Niemann–Pick C disease in Spain: clinical spectrum and development of a disability scale. J Neurol Sci 249:1–6
doi: 10.1016/j.jns.2006.05.054
Schmitz-Hübsch T, du Montcel ST, Baliko L et al (2006) Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66:1717–1720
doi: 10.1212/01.wnl.0000219042.60538.92
Schmitz-Hübsch T, Giunti P, Stephenson DA et al (2008) SCA Functional Index: a useful compound performance measure for spinocerebellar ataxia. Neurology 71:486–492
doi: 10.1212/01.wnl.0000324863.76290.19
Quinn TJ, Dawson J, Walters MR, Lees KR (2008) Variability in modified Rankin scoring across a large cohort of international observers. Stroke 39:2975–2979
doi: 10.1161/STROKEAHA.108.515262
EuroQol Group (2017) EQ-5D instruments|about EQ-5D. 2017. 2017. https://euroqol.org/eq-5d-instruments/eq-5d-5l-about . Accessed 15 Feb 2020
Hodges JL, Lehmann EL (1963) Estimates of location based on rank tests. Ann Math Stat 34:598–611
doi: 10.1214/aoms/1177704172
Koch MW, Cutter G, Stys PK, Yong VW, Metz LM (2013) Treatment trials in progressive MS–current challenges and future directions. Nat Rev Neurol 9:496–503
doi: 10.1038/nrneurol.2013.148
Hegdekar N, Lipinski MM, Sarkar C (2021) N-Acetyl-L-leucine improves functional recovery and attenuates cortical cell death and neuroinflammation after traumatic brain injury in mice. Sci Rep 11:9249
doi: 10.1038/s41598-021-88693-8
Kaya E, Smith DA, Smith C, Boland B, Strupp M, Platt FM (2020) Beneficial effects of acetyl-DL-leucine (ADLL) in a mouse model of Sandhoff disease. J Clin Med 9:1050
doi: 10.3390/jcm9041050
Perez-Lloret S, van de Warrenburg B, Rossi M et al (2020) Assessment of ataxia rating scales and cerebellar functional tests: critique and recommendations. Mov Disord. https://doi.org/10.1002/mds.28313 ((published online Oct 6))
doi: 10.1002/mds.28313
pubmed: 33022077
Yanjanin NM, Vélez JI, Gropman A et al (2010) Linear clinical progression, independent of age of onset, in Niemann–Pick disease, type C. Am J Med Genet B Neuropsychiatr Genet 153B:132–140
pubmed: 19415691
pmcid: 2798912